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United States Patent |
5,607,939
|
Kato
,   et al.
|
March 4, 1997
|
Condensed heterocyclic compounds, their production and use
Abstract
The compound
##STR1##
wherein ring A represents a benzene ring; Ar represents an aromatic group;
R.sup.1 and R.sup.2 independently represent hydrogen, acyl or hydrocarbon
group or R.sup.1 and R.sup.2 taken together with the adjacent nitrogen
atom represent a nitrogen-containing heterocyclic group; m represents an
integer of 1 to 6; n represents an integer of 2 to 3; ----- represents a
single bond or a double bond; X stands for --O-- or --NR.sup.3 -- in which
R.sup.3 represents hydrogen, acyl or hydrocarbon group where ----- is a
single bond or .dbd.N-- where ----- is a double bond has excellent GnRH
receptor antagonizing activity, calcium antagonizing and monoamine-uptake
inhibiting activities and and value as a prophylactic/therapeutic drug for
sex hormone-dependent diseases and for central nervous system diseases.
Inventors:
|
Kato; Kaneyoshi (Hyogo, JP);
Sugiura; Yoshihiro (Nara, JP);
Kato; Koichi (Ibaraki, JP);
Nagai; Yasuo (Osaka, JP)
|
Assignee:
|
Takeda Chemical Industries, Ltd. (Osaka, JP)
|
Appl. No.:
|
428499 |
Filed:
|
April 25, 1995 |
Foreign Application Priority Data
| Apr 28, 1994[JP] | 6-092769 |
| Apr 28, 1994[JP] | 6-114054 |
Current U.S. Class: |
514/278; 514/212.02; 514/217.03; 514/233.5; 514/253.03; 514/253.05; 514/254.11; 514/316; 514/320; 514/323; 514/337; 514/367; 514/399; 514/414; 514/444; 514/459; 540/594; 540/596; 544/151; 544/364; 544/368; 544/376; 546/17; 546/150; 546/187; 546/196; 546/201; 546/272.7; 546/276.4; 546/277.1; 546/281.7; 546/282.7; 548/159; 548/311.4; 548/454; 549/60; 549/406 |
Intern'l Class: |
A61K 031/44; C07D 401/06 |
Field of Search: |
548/311.4,454,159
546/201,150,187,269,17,196
544/364,376,151,368
540/594,596
549/406,60
514/399,233.5,414,459,255,278,320,212,213,444,337,316,323,367
|
References Cited
U.S. Patent Documents
2759936 | Aug., 1956 | Specter | 260/247.
|
3553218 | Jan., 1971 | Unger et al. | 260/286.
|
3880885 | Apr., 1975 | Houlihan et al. | 260/343.
|
4247553 | Jan., 1981 | McCall | 424/250.
|
4650884 | Mar., 1987 | Bogeso | 549/467.
|
Foreign Patent Documents |
1374337 | Nov., 1974 | GB.
| |
Other References
McCall, J. M., 1-(Alkylamino)isochromans: Hypotensives with Preipheral and
Central Activities, J. Med. Chem., 25, pp. 75-81 1982.
|
Primary Examiner: McKane; Joseph
Assistant Examiner: Myers, Jr.; Richard S.
Attorney, Agent or Firm: Fitzpatrick, Cella, Harper & Scinto
Claims
What is claimed is:
1. A compound of the formula
##STR552##
wherein ring A represents a benzene ring which may be substituted with 1
to 3 substituents selected from the group consisting of halogen atom,
C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be
halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl, C.sub.1-7 acylamino and methylenedioxy;
Ar represents (i) a C.sub.6-14 aryl or (ii) a 5- or 6-membered
heteroaromatic group having 1 to 3 hetero-atoms selected from the group
consisting of nitrogen, oxygen and sulfur, each of which groups (i) and
(ii) may be substituted with 1 to 3 substituents selected from the group
consisting of halogen atom, C.sub.1-6 alkyl which may be halogenated,
C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may
be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxy-carbonyl, C.sub.1-7 acylamino and methylenedioxy;
R.sup.1 and R.sup.2 independently represent (i) hydrogen atom, (ii) a group
of the formula: --CO--R, --CONH--R, --SO.sub.2 --R or --CO--OR wherein R
represents a C.sub.1- 6 alkyl, C.sub.2-6 alkenyl, C2-6 alkynyl, C.sub.3-6
cycloalkyl, C.sub.6-14 aryl or C.sub.7-16 aralkyl group which may be
substituted with 1 to 3 substituents selected from the group consisting of
halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which
may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro,
cyano, sulfo, hydroxy, amino, mono(C.sub.1-6) alkylamino,
di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxy-carbonyl, C.sub.1-7
[acylamnio] acylamino, methylenedioxy, oxo, thioxo, phenyl, phenylamino,
phenyloxy and methylenedioxyphenyloxy, or (iii) a C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.6-14 aryl or
C.sub.7-16 aralkyl group which may be substituted with 1 to 3 substituents
selected from the group consisting of halogen, C.sub.1-6 alkyl which may
be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6 )alkylamino, di(C.sub.1-6 )alkylamino, carboxy, C.sub.1-6
alkoxy-carbonyl and C.sub.1-7 acylamino, methylenedioxy, oxo, thioxo,
phenyl, phenylamino, phenyloxy and methylenedioxyphenyloxy;
or R.sup.1 and R.sup.2 taken together with the adjacent nitrogen atoms
represent (i) a 5- or 6-membered nitrogen-containing hetero-aromatic group
having 1 to 3 hetero-atoms selected from the group consisting of nitrogen,
oxygen and sulfur, which hetero-aromatic group may be substituted with 1
to 3 substituents selected from the group consisting of halogen, C.sub.1-6
alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated,
C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo,
hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6 )alkylamino,
carboxy, C.sub.1-6 alkoxy-carbonyl and C.sub.1-7 acylamino,
##STR553##
wherein ring B may be substituted with 1 or 2 oxo groups and may be fused
to one benzene ring which may be substituted with 1 to 3 substituents
selected from the group consisting of halogen atoms, C.sub.1-6 alkyl which
may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxy-carbonyl and C.sub.1-7 acylamino,
p represents an integer of 4 to 7;
##STR554##
wherein Z represents --O--, >CH--W or >N--W in which W represents (a)
hydrogen atom, (b) a C.sub.6-14 aryl or C.sub.7-16 aralkyl group, which
aryl or aralkyl group may be substituted with 1 to 3 substituents selected
from the group consisting of halogen atom, C.sub.1-6 alkyl which may be
halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxy-carbonyl and C.sub.1-7 acylamino or (c) a 5- to 11-membered
aromatic or non-aromatic heterocyclic group containing 1 to 3 hetero atoms
selected from the group consisting of nitrogen, sulfur and oxygen atoms in
addition to carbon atoms, which may be substituted with 1 to 3
substituents selected from the group consisting of halogen, C.sub.1-6
alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated,
C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo,
hydroxy, amino, mono(C.sub.1-6 )alkylamino, di(C.sub.1-6)alkylamino,
carboxy, C.sub.1-6 alkoxy-carbonyl and C.sub.1-7 acylamino,
methylenedioxy, oxo, thioxo, phenyl, phenylamino, phenyloxy and
methylenedioxyphenyloxy,
##STR555##
wherein ring D represents (a) a benzene ring or (b) a 5- or 6-membered
heteroaromatic ring having 1 to 3 hetero-atoms selected from nitrogen,
oxygen and sulfur, each of which rings (a) and (b) may be substituted with
1 to 3 substituents selected from the group consisting of halogen atoms,
C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be
halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano,
sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino,
carboxy, C.sub.1-6 alkoxy-carbonyl and C.sub.1-7 acylamino,
Y represents --CH.sub.2 --, --CO-- or --CH(OH)--,
s and t individually represent an integer of 1 to 3, or
##STR556##
wherein ring D.sup.b represents a benzene ring which may be substituted
with 1 to 3 substituents selected from the group consisting of halogen
atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may
be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro,
cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino,
di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7
acylamino, Y is --CH.sub.2 --, --CO-- or --CH(OH)--;
m represents an integer of 1 to 6;
n represents 1;
----- represents a single bond;
X represents --O--;
or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1, wherein Ar represents a phenyl group
which may be substituted with 1 to 3 substituents selected from the group
consisting of halogen atom, C.sub.1-6 alkyl which may be halogenated,
C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may
be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxy-carbonyl and C.sub.1-7 acylamino.
3. A compound as claimed in claim 1, wherein R.sup.1 represents hydrogen
atom and R.sup.2 represents a aralkyl which may be substituted with 1 to 3
substituents selected from the group consisting of halogen atom, C.sub.1-6
alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated,
C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo,
hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino,
carboxy, C.sub.1-6 alkoxy-carbonyl and C.sub.1-7 acylamino.
4. A compound as claimed in claim 1, wherein R.sup.1 and R.sup.2 taken
together with the adjacent nitrogen atom form
##STR557##
wherein ring D.sup.a represents a benzene ring which may be substituted
with 1 to 3 substituents selected from the group consisting of halogen
atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may
be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro,
cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino,
di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxy-carbonyl and C.sub.1-7
acylamino, Y.sup.a represents --CH.sub.2 -- or --CO--.
5. A process for producing the compound of claim 1, wherein X is --O-- or a
salt thereof, which comprises reacting a compound of the formula
##STR558##
wherein L represents a leaving group and the other variables are as
defined in claim 1, or a salt thereof, with a compound of the formula
##STR559##
wherein the symbols are as defined in claim 1, or a salt thereof.
6. A method of administering a gonadotropin-releasing hormone antagonistic
composition, which comprises the steps of:
selecting a composition comprising a compound as claimed in claim 1, or a
salt thereof and a pharmaceutically acceptable carrier, excipient or
diluent; and
administering said composition to a patient.
7. A method as claimed in claim 6, wherein said composition is administered
for preventing or treating a sex hormone-dependent disease.
8. A method as claimed in claim 7, wherein the sex hormone-dependent
disease is prostatic cancer, uterus cancer, breast cancer or pituitary
tumor.
9. A method as claimed in claim 7, wherein the sex hormone-dependent
disease is prostatic hypertrophy, endometriosis, hysteromyoma or
precocious puberty.
10. A method of inducing ovulation, comprising the steps of selecting a
composition which comprises an effective amount of a compound as claimed
in claim 1, or a salt thereof, and a pharmaceutically acceptable carrier,
excipient or diluent; and
administering said composition to a female human.
11. A method of achieving contraception comprising the steps of selecting a
composition which comprises an effective amount of a compound as claimed
in claim 1, or a salt thereof; and a pharmaceutically acceptable carrier,
excipient or diluent; and administering said composition to a female
human.
12. A method of regulating menstrual cycle, comprising the steps of
selecting a composition which comprises an effective amount of a compound
as claimed in claim 1, or a salt thereof, and a pharmaceutically
acceptable carrier, excipient or diluent; and
administering said composition to a female human.
13. A method for antagonizing a gonadotropin-releasing hormone in mammals
which comprises administrating to a subject in need an effective amount of
the compound as claimed in claim 1.
14. A method for treating a sex hormone-dependent disease in mammals which
comprises administrating to a subject in need an effective amount of the
compound as claimed in claim 1.
15. A method as claimed in claim 14, wherein the sex hormone-dependent
disease is prostatic cancer, uterus cancer, breast cancer or pituitary
tumor.
16. A method as claimed in claim 14, wherein the sex hormone-dependent
disease is prostatic hypertrophy, endometriosis, hysteromyoma or
precocious puberty.
17. A method for inducing ovulation in mammals which comprises
administrating to a subject in need an effective amount of the compound as
claimed in claim 1.
18. A method for achieving contraception in mammals which comprises
administrating to a subject in need an effective amount of the compound as
claimed in claim 1.
19. A method for regulating a menstrual cycle in mammals which comprises
administrating to a subject in need an effective amount of the compound as
claimed in claim 1.
20. 3,4-dihydro-6,7-
dimethoxy-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[naphthalene-2(1H),2'-
piperidine] or a salt thereof.
21. 4-phenyl-4-{3-[1-(1,2,3,4-tetrahydronaphthylamino)]propyl]isochroman or
a salt thereof.
22. A compound as claimed in claim 1, wherein ring B fused to one benzene
ring represents
##STR560##
wherein G represents 1 to 3 substituents selected from the group
consisting of halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy.
23. A compound as claimed in claim 1, wherein R.sup.1 and R.sup.2 taken
together with adjacent nitrogen atom form
##STR561##
wherein G represents 1 to 3 substituents independently selected from the
group consisting of halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a novel condensed heterocyclic compounds which
have excellent gonadotropin-releasing hormone (GnRH) receptor antagonizing
activity, as well as processes for producing the compounds, pharmaceutical
compositions containing the compound, and medical uses for the
pharmaceutical compositions.
The compounds of this invention also have calcium-antagonizing and
monoamine-uptake inhibiting activities and are therefore useful as a
prophylactic/therapeutic drug for acute and chronic central nervous system
disorders and CNS-related diseases, such as dysmnesia.
2. Related Prior Art
Gonadotropin-releasing hormone (GnRH) is a deca-peptide consisting of 10
amino acids produced in the hypothalamus. It is known that this hormone
regulates secretion of luteinizing hormone (LH) and follicle stimulating
hormone (FSH) through receptors which are considered to be present in the
anterior lobe of the pituitary gland. GnRH thereby exhibits several
physiological activities including induction of ovulation. Since an
antagonist or agonist that is specific to such receptors is expected to
regulate the hormonal activities of GnRH produced from the hypothalamus
and control the secretion of anterior pituitary hormones (including LH or
FSH, which inhibits the secretion of estrogen in female or testosteron in
male) the prophylactic or therapeutic effect on anterior pituitary
hormone-dependent diseases can be expected.
Since the discovery of gonadotropin-releasing hormone in 1971, a large
number of its congeners have been synthesized in the expectation of
agonistic or antagonistic activity. For example, leuprolerin acetate is a
compound which has a higher affinity for GnRH receptors and is less easily
metabolized than native GnRH.
Repeated administration of leuprolerin acetate, which is 20 to 50-fold as
active as native GnRH, causes the so-called receptor down regulation to
decrease the release and production of gonadotropin-releasing hormone in
the pituitary gland and, for example, reduce the response of the testis to
gonadotropin and accordingly, reduce its testosterone-producing capacity
to the castrated level or reduce estrogen-producing capacity in the ovary.
It is known that the compound consequently shows an antitumor effect on
hormone-dependent cancer, for example cancer of the prostate. In fact,
leuprolerin acetate is in broad clinical use as a therapeutic agent for
prostatic cancer, breast cancer and hystromyoma, as well as endometriosis,
among other diseases.
However, these GnRH agonist are peptides which are poorly absorbed after
oral administration and and therefore restricted in dosage form. Moreover,
they develop agonistic activity transiently before the onset of efficacy
following administration so that the steroidal sex hormone concentration
in blood increases, sometimes causing a transitory exacerbation such as
ostealgia in some cases.
Accordingly, attempts are being made with the object of developing GnRH
antagonists which provide therapeutic efficacy, but which are free of the
above-mentioned side effects.
As compounds having such GnRH antagonizing activity, there is a list of
known compounds such as cyclic hexapeptide derivatives (U.S. Pat. No.
4,659,691) and bicyclic peptide derivatives (J. Med. Chem., 36, 3265-3273,
1993), all of which have been developed with attention focused on the
spatial configuration of GnRH. However, since these compounds are
peptides, the perennial problems such as poor oral absorption and poor
stability in the patient remain to be solved.
Meanwhile, synthesis of non-peptide compounds having GnRH receptor
antagonizing activity has also been undertaken. U.S. Pat. No. 4,678,784
describes benzazepine compounds of the formula
##STR2##
[wherein R.sup.1 represents an amino functional group of --NR.sup.3
R.sup.4, 4-morpholino,
##STR3##
R.sup.2 represents hydrogen, alkoxy, alkyl, trifluoromethyl, halogen,
nitro, hydroxy or dialkylamino;
R.sup.4 and R.sup.4 independently represent hydrogen, alkyl, or alkyl
substituted by hydroxyl, halogen or alkoxy;
m is equal to 0 or 1;
n is equal to 0, 1 or 2;
R.sup.5 represents hydroxyl, alkyl, halogen, carboxy, alkoxycarbonyl, or
alkyl substituted by hydroxyl, halogen, alkoxy or phenyl; and
R.sup.6 represents hydrogen, alkyl, carboxy, alkoxycarbonyl or phenyl;
R.sup.7 represents hydrogen, alkyl, alkoxycarbonyl, or alkyl substituted by
hydroxyl, halogen, alkoxy, phenoxy or alkoxycarbonyl]. Journal of Medical
Chemistry 32, 2036-2038, 1989 describes and mentions that compounds of the
formula
##STR4##
wherein R represents
##STR5##
have LHRH (luteinizing hormone-releasing hormone) antagonizing activity.
Meanwhile, it is known that in cerebrovascular disorders or head injury,
neuron-excitatory amino acids (among other factors) elevate intracellular
Ca.sup.2+ concentration This elevation of Ca.sup.2+ concentration causes
activation of Ca.sup.2+ -dependent enzymes, which results in the
over-excitment and consequent death of neurons, leading to aggravation of
symptoms.
For the treatment of these diseases and specifically for controlling an
excessive elevation of intracellular Ca.sup.2+ concentration, a variety
of calcium channel blockers represented by dihydropyridines have been
employed. However, these non-selective Ca.sup.2+ channel blockers act
peripherally on the heart, blood vessels, etc. as well as the central
nervous system. Moreover, some of them, such as flunarizine, have
extrapyramidal side effects.
Recently, in dementia accompanied by shedding of neurofilaments, for
example in Alzheimer's disease, the role of abnormal intracellular calcium
ion concentration in the mechanism of the cytotoxicity of the etiologic
factor .beta.-amyloid protein has been pointed out [Mark P. Mattson et
al., Trends in NeuroScience, 16, 409]. Against the above background, it is
now considered that a CNS-selective calcium ion antagonist would normalize
the calcium ion homeostasis in the brain nerve cell and thereby show
prophylactic and therapeutic efficacy for dementia.
WO92/06172 describes a piperidine derivative having CNS-selective calcium
antagonistic activity.
Meanwhile, U.S. Pat. No. 2,759,936 describes, as an anticonvulsant, a
compound of the formula
##STR6##
[wherein R represents C.sub.1-6 alkyl; X represents C.sub.2-4 alkylene; B
represents di (lower) alkyl, piperidino, morpholino, pyrrolidino,
N'-alkylpiperazino or pipecolino].
A compound of the formula
##STR7##
[wherein R.sup.1 and R.sup.2 independently represent hydrogen or C.sub.1-4
akyl] is reported (U.S. Pat. No. 3,553,218),
a compound of the formula
##STR8##
[wherein R.sup.1 represents hydrogen, C.sub.1-6 alkyl or phenyl; R.sup.2
represents
##STR9##
(A represents alkylene; R.sup.5 and R.sup.6 independently represent alkyl
or, taken together with the nitrogen atom, represent a 5- through
7-membered ring); R.sup.3 and R.sup.4 independently represent C.sub.1-4
alkoxy] as a cardiovascular drug is reported (U.S. Pat. No. 4,118,494),
a compound of the formula
##STR10##
is reported (U.S. Pat. No. 4,650,884), and
a compound of the formula
##STR11##
[wherein R.sub.1, R.sub.2 and R.sub.3 independently represent hydrogen,
hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, CF.sub.3 or
methylenedioxy; R.sub.4 represents hydrogen or C.sub.1-4 alkyl; A
represents a bond, C.sub.1-6 alkylene or alkylidene; where Y is a bond, B
represents C.sub.1-6 alkylene or alkylidene; where Y is O, S or NR.sup.5,
B represents C.sub.2-6 alkylene; X represents CH or N; R.sub.5 represents
hydrogen or C.sub.1-4 alkyl] as a therapeutic drug for angina pectoris and
myocardial infarction which has intracellular calcium-antagonizing
activity is reported (U.S. Pat. No. 5,238,939).
SUMMARY OF THE INVENTION
This invention has for its object to provide a novel condensed heterocyclic
compound (or salt thereof) having excellent gonadotropin-releasing hormone
receptor antagonistic activity, calcium-antagonizing and/or
monoamine-uptake inhibiting activities.
The inventors of this invention explored compounds having the following
nuclear structures and discovered that compounds having both an aromatic
group and a nitrogen-terminated alkyl group in the (3+n) position of the
above nuclear structure have excellent gonadotropin-releasing hormone
receptor antagonistic, calcium-antagonizing and monoamine-uptake
inhibiting activities and exhibit minimal toxicity.
##STR12##
(n represents an integer of 1 to 3.)
This invention has been developed on the basis of the above finding.
DETAILED DESCRIPTION OF THE INVENTION
The present invention generally relates to: a compound of the formula
##STR13##
wherein ring A represents a benzene ring which may be substituted, Ar
represents an aromatic group which may be substituted,
R.sup.1 and R.sup.2 independently represent hydrogen atom, acyl group or
hydrocarbon group (residue) which may be substituted or R.sup.1 and
R.sup.2 taken together with the adjacent nitrogen atom represent a
nitrogen-containing heterocyclic group,
m represents an integer of 1 to 6,
n represents an integer of 1 to 3,
----- represents a single bond or a double bond,
X is --O-- or --NR.sup.3 -- (R.sup.3 represents hydrogen atom, acyl group
or hydrocarbon group which may be substituted) where ----- is a single
bond, or X is .dbd.N-- where ----- is a double bond, or a salt thereof.
As used in this specification, the term "benzene ring which may be
substituted" means a benzene ring which may be substituted by, for
example, halogen, alkyl which may be halogenated, alkoxy which may be
halogenated, alkylthio which may be halogenated, nitro, cyano, sulfo,
hydroxy, amino, mono- or di(C.sub.1-6)alkylamino (e.g. methylamino,
ethylamino, propylamino, dimethylamino, diethylamino, etc.), carboxy,
C.sub.1-6 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, etc.), C.sub.1-7
acylamino (e.g. formylamino, acetylamino, propionylamino, butyrylamino,
benzoylamino, etc.) and methylenedioxy, among others. However, among the
above-mentioned substituent groups, nitro, cyano and sulfo are excluded in
the case of the "benzene ring which may be substituted" for the ring A.
The substituent group may be present in any substitutable position on the
benzene ring and may number 1 to 3. Moreover, where the number of
substituents is at least 2, they may be the same or different.
The "aromatic group" of the term "aromatic group which may be substituted"
as used throughout this specification includes aromatic hydrocarbon groups
and heteroaromatic groups, among others.
The "aromatic hydrocarbon group" in this context is a monocyclic or
condensed polycyclic aromatic hydrocarbon group, including C.sub.6-4 aryl
groups such as phenyl, naphthyl, indenyl, anthryl, etc. Phenyl is
particularly preferred.
The "heteroaromatic group" in the above context is a 5- or 6-membered
monocyclic heteroaromatic group having preferably 1-3 hetero-atoms of 1 or
2 kinds as selected from among nitrogen, oxygen and sulfur in addition to
carbon as ring members, which may be fused to aromatic rings, such as a
benzene ring, to form a bicyclic or tricyclic heteroaromatic group. Thus,
5- or 6-membered monocyclic heteroaromatic groups having 1-3 hetero-atoms
selected from among nitrogen, oxygen and sulfur in addition to carbon as
ring members, such as 2-thienyl, 3-thienyl, 2-pyridyl, 4-pyridyl, 2-furyl,
3-furyl, 4-quinolyl, 8-quinolyl, 4-isoquinolyl, pyrazinyl, 2-pyrimidinyl,
3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 1-indolyl,
2-isoindolyl, etc., and bicyclic heteroaromatic groups formed as one
benzene ring is fused to the respective monocyclic groups can be
mentioned, among others.
Particularly, 5- or 6-membered heterocyclic groups having 1-3 hetero-atoms
selected from among nitrogen, oxygen and sulfur in addition to carbon as
ring members (e.g. 2-pyridyl, 4-pyridyl, etc.) are preferred.
The substituent groups that may be possessed by the "aromatic group" are
similar to those mentioned for the "benzene ring which may be
substituted".
The substituent group may be present in any substitutable position on the
heteroaromatic group and may number 1 through 3. When the number of
substituents is at least 2, they may be the same or different.
The "hydrocarbon group" of the term "hydrocarbon group which may be
substituted" as used throughout this specification means any of the groups
listed below under (1) or (2), among others.
(1) acyclic hydrocarbon groups:
a) C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl, etc.)
b) C.sub.2-6 alkenyl (e.g. vinyl, allyl, isopropenyl, butenyl, isobutenyl,
sec-butenyl, etc.)
c) C.sub.2-6 alkinyl (e.g. propargyl, ethinyl, butinyl, 1hexinyl, etc.)
(2) Cyclic hydrocarbon groups:
a) C.sub.3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, etc.); cyclohexyl may be fused to a benzene ring which may be
substituted by C.sub.1-4 alkyl or C.sub.1- 4 alkoxy
b) C.sub.6-14 aryl (e.g. phenyl, tolyl, xylyl, 1-naphthyl, 2-naphthyl,
biphenyl, 2-indenyl, 2-anthryl, etc.); phenyl is preferred
c) C.sub.7-16 aralkyl (e.g. benzyl, phenethyl, diphenylmethyl,
triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-diphenylethyl,
3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.); benzyl is preferred
The substituent groups which may be possessed by the "hydrocarbon group
which may be substituted" are oxo, thioxo, phenyl, phenylamino, phenyloxy
and methylenedioxyphenyloxy group, in addition to similar to those
mentioned for the "benzene ring which may be substituted".
The substituent group may be present in any substitutable position on the
hydrocarbon group and may number 1 to 3. Where the number of substituents
is not less than 2, they may be the same or different.
The term "acyl" as used throughout this specification means, among others,
--CO--R, --CONH--R, --SO.sub.2 --R or --CO--OR wherein R represents a
hydrocarbon group which may be substituted.
The "hydrocarbon group which may be substituted" for R can be any of those
groups mentioned hereinbefore. For example, formyl, acetyl, propionyl,
butyryl, valeryl, acryloyl, propiolyl, benzoyl, nicotinoyl,
methanesulfonyl, ethanesulfonyl, benzenesulfonyl and toluenesulfonyl can
be mentioned as acyl group.
The term "halogen" is typically used in this specification to mean
fluorine, chlorine, bromine or iodine. Fluorine and chlorine are
preferred.
Preferably, ring A is a benzene ring which may be substituted with 1 to 3
substituents selected from the group consisting of halogen atom, C.sub.1-6
alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated,
C.sub.1-6 alkylthio which may be halogenated, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino; and
Ar is preferably (i) a C.sub.6-14 aryl (most preferably, benzene) or (ii)
5- or 6-membered heteroaromatic group having 1 to 3 hetero-atoms selected
from nitrogen, oxygen and sulfur, which may be substituted with 1 to 3
substituents selected from the group consisting of halogen atom, C.sub.1-6
alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated,
C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo,
hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino,
carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino.
The hydrocarbon group which may be substituted is preferably a C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkinyl, C.sub.3-6 cycloalkyl,
C.sub.6-14 aryl or C.sub.7-16 aralkyl group which may be substituted with
1 to 3 substituents selected from the group consisting of halogen,
C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be
halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano,
sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino,
carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino; and
the nitrogen-containing heterocyclic group is preferably
(i) a 5- or 6-membered nitrogen-containing heteroaromatic group having 1 to
3 hetero-atoms selected from nitrogen, oxygen and sulfur, which may be
substituted with 1 to 3 substituents selected from the group consisting of
halogen atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy
which may be halogenated, C.sub.1-6 alkylthio which may be halogenated,
nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino,
di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7
acylamino,
(ii)
##STR14##
wherein ring B may be substituted by two oxo groups and may be fused to
one benzene ring which may be substituted with 1 to 3 substituents
selected from the groups consisting of halogen atom, C.sub.1-6 alkyl which
may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di (C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and acylamino, p represents an integer of 4 to 7,
(iii)
##STR15##
wherein Z represents --O--, >CH--W or >N--W (W represents (a) hydrogen
atom or (b) a C.sub.6-14 aryl or C.sub.7-16 aralkyl group, which may be
substituted with 1 to 3 substituents selected from the group consisting of
halogen atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy
which may be halogenated, C.sub.1-6 alkylthio which may be halogenated,
nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino,
di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxy-carbonyl and C.sub.1-7
acylamino, or
(iv)
##STR16##
wherein ring D represents (a) a benzene ring or (b) 5- or 6-membered
heteroaromatic group having 1 to 3 hetero-atoms selected from nitrogen,
oxygen and sulfur, which may be substituted with 1 to 3 substituents
selected from the group consisting of halogen atom, C.sub.1-6 alkyl which
may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino,
Y represents --CH.sub.2 --, --CO-- or --CH(OH)--,
s and t each represents an integer of 1 to 3.
Ar is also preferably a phenyl group which may be substituted with 1 to 3
substituents selected from the group consisting of halogen atom, C.sub.1-6
alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated,
C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo,
hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino,
carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino;
Other preferred embodiments are when: R.sup.1 represents hydrogen atom and
R.sup.2 represents a C.sub.7-16 aralkyl which may be substituted with 1 to
3 substituents selected from the group consisting of halogen atom,
C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may be
halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro, cyano,
sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino,
carboxy, C.sub.1-6 alkoxy-carbonyl and C.sub.1-7 acylamino; or
R.sup.1 and R.sup.2 taken together with the adjacent nitrogen atom form
##STR17##
wherein ring D.sup.a represents a benzene ring which may be substituted
with 1 to 3 substituents selected from the group consisting of halogen
atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may
be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro,
cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino,
di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7
acylamino, Y.sup.a represents --CH.sub.2 -- or --CO--;
Also preferred are those compounds in which:
----- represents a single bond and X represents --O--; or
----- represents a single bond and X represents --NR.sup.3a -- in which
R.sup.3a represents hydrogen atom or C.sub.1-6 alkyl group;
Other preferred embodiments are when: ring A is a benzene ring which may be
substituted with 1 to 3 substituents selected from the group consisting of
halogen atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy
which may be halogenated, C.sub.1-6 alkylthio which may be halogenated,
hydroxy, amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino,
carboxy, C.sub.1-6 alkoxy-carbonyl, C.sub.1-7 acylamino and
methylenedioxy;
the hydrocarbon group which may be substituted is a C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkinyl, C.sub.3-6 cycloalkyl, C.sub.6-14
aryl or C.sub.7-16 aralkyl group which may be substituted with 1 to 3
substituents selected from the group consisting of halogen, C.sub.1-6
alkyl which may be halogenated, C.sub.1-6 alkoxy which may be halogenated,
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxy-carbonyl, C.sub.1-7 acylamino, oxo, thioxo, phenyl, phenylamino,
phenyloxy and methylenedioxyphenyloxy; or
the nitrogen-containing heterocyclic group is
(i) a 5- or 6-membered nitrogen-containing heteroaromatic group having 1 to
3 hetero-atoms selected from nitrogen, oxygen and sulfur, which may be
substituted with 1 to 3 substituents selected from the group consisting of
halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which
may be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro,
cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino,
di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7
acylamino,
(ii)
##STR18##
wherein ring B may be substituted by 1 or 2 oxo groups and may be fused to
one benzene ring which may be substituted with 1 to 3 substituents
selected from the groups consisting of halogen atom, C.sub.1-6 alkyl which
may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and acylamino, p represents an integer of 4 to 7,
(iii)
##STR19##
wherein Z represents --O--, >CH--W or >N--W (W represents (a) hydrogen
atom, (b) a C.sub.6-14 aryl or C.sub.7-16 aralkyl group, which may be
substituted with 1 to 3 substituents selected from the group consisting of
halogen atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy
which may be halogenated, C.sub.1-6 alkylthio which may be halogenated,
nitro, cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino,
di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxy-carbonyl and C.sub.1-7
acylamino or (c) a heterocyclic group which may be substituted),
(iv)
##STR20##
wherein ring D represents (a) a benzene ring or (b) a 5- or 6-membered
heteroaromatic group having 1 to 3 hetero-atoms selected from nitrogen,
oxygen and sulfur, which may be substituted with 1 to 3 substituents
selected from the group consisting of halogen atom, C.sub.1-6 alkyl which
may be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino,
Y represents --CH.sub.2 --, --CO-- or --CH(OH)--,
s and t each represents an integer of 1 to 3, or
(v)
##STR21##
wherein ring D.sup.b represents a benzene ring which may be substituted
with 1 to 3 substituents selected from the group consisting of halogen
atom, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy which may
be halogenated, C.sub.1-6 alkylthio which may be halogenated, nitro,
cyano, sulfo, hydroxy, amino, mono(C.sub.1-6)alkylamino,
di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7
acylamino, Y is --CH.sub.2 --, --CO-- or --CH(OH)--.
These compounds and others according to the formula
##STR22##
wherein all the symbols are as defined above or a salt thereof, may be
produced by reacting a compound of the formula
##STR23##
wherein L represents a leaving group and the other symbols are as defined
above, or a salt thereof, with a compound of the formula
##STR24##
wherein the symbols are as defined above, or a salt thereof.
These compounds and others according to the formula
##STR25##
wherein all the symbols are as defined above, or a salt thereof, may be
produced by subjecting a compound of the formula
##STR26##
wherein all the symbols are as defined above, or a salt thereof, to
cyclization.
The term "alkyl which may be halogenated" as used in this specification
means any of C.sub.1-6 alkyl groups substituted by 1-3 halogen atoms (e.g.
fluorine, chlorine, iodine, etc.) (for example, methyl, chloromethyl,
difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,
isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,
6,6,6-trifluorohexyl, etc.). Among others, C.sub.1-4 alkyl groups
optionally substituted by 1-3 halogen atoms (e.g. fluorine, chlorine,
bromine, etc.) (for example, methyl, chloromethyl, difluoromethyl,
trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,
4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, etc.) are
preferable.
The term "alkoxy which may be halogenated" is used in this specification to
mean any of C.sub.1-6 alkoxy groups optionally substituted by 1-3 "halogen
atoms" similar to those mentioned above, such as methoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,
butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy,
etc. Among others, C.sub.1-4 alkoxy groups optionally substituted by 1-3
"halogen atoms" similar to those mentioned above, such as methoxy,
difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy,
isopropoxy, butoxy, 4,4,4trifluorobutoxy, isobutoxy, sec-butoxy, etc are
preferable.
The term "alkylthio which may be halogenated" is used in this specification
to mean any of C.sub.1-6 alkylthio groups optionally substituted by 1-3
"halogen atoms" similar to those mentioned above, such as methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio,
etc., and preferably C.sub.1-4 alkylthio groups optionally substituted by
1-3 "halogen atoms" similar to those mentioned above, such as methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio, 4,4,4-trifluorobutylthio and so on.
The phrase "which may be halogenated" as used in this specification is
equivalent to "which may be substituted by 1-3 halogen atoms (e.g.
fluorine, chlorine, bromine, etc.)".
The "heterocyclic group" of the term "heterocyclic group which may be
substituted" as used throughout this specification include a 5- to
11-membered aromatic or non-aromatic heterocyclic group containing 1 to 3
hetero atoms selected from a nitrogen, sulfur and oxygen atom in addition
to carbon atoms. Such groups include a 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-quinolyl, 4-quinolyl, 8quinolyl,
3-isoquinolyl, 4-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl,
1-imidazolyl, 2-imidazolyl, 1-pyrazolyl, 2-thiazolyl, 4-thiazolyl,
5-thiazolyl, 3isothiazolyl, 4-isothiazolyl, 3-isoxazolyl, 3-pyridazinyl,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyridon-1-yl,
3-pyridion-1-yl, 1-imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl,
piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 2-morpholinyl,
3-morpholinyl, morpholino, 1-pipeprazinyl, 2-piperazinyl, 1-isoindolyl,
2-isoindolyl, 1-indoly, 3-indolyl, phthalimido, 2-benzothiazolyl and
2,3,4,5-tetrahydro-(1H)-3-benzazepinyl group.
The substituent groups which may be possessed by the "heterocyclic group"
are similar to those mentioned for the "hydrocarbon group which may be
substituted".
The substituent group may be present in any substitutable position on the
heterocyclic group and may number 1 to 3. Where the number of substituents
is at least 2, they may be the same or different.
The term "nitrogen-containing heterocyclic group" is used throughout this
specification to mean any of the following groups, among others.
(i) 5- or 6-membered nitrogen-containing heteroaromatic groups having 1-3
hetero-atoms selected from nitrogen, oxygen and sulfur in addition to
carbon as ring members, such as
##STR27##
and so on.
(ii)
##STR28##
wherein ring B may be substituted by 1 or 2 oxo groups and/or be fused to
one benzene ring which may be substituted; p represents an integer of 4 to
7; the "benzene ring which may be substituted" mentioned just above is as
defined hereinbefore. Among others, preferred are
##STR29##
and so on. In the above formulae, G represents halogen (e.g. fluorine,
chlorine, etc.), C.sub.1-6 alkyl (e.g. methyl, ethyl, isopropyl, etc.), or
C.sub.1-6 alkoxy (e.g. methoxy, ethoxy, isopropoxy), etc., for instance.
(iii)
##STR30##
In the above formula, Z represents oxygen, >CH--W or >N--W, wherein W
represents (a) hydrogen, (b) a C.sub.6-14 aryl (e.g. phenyl) or C.sub.7-16
aralkyl (e.g. benzyl) group which may be substituted or (c) heterocyclic
group which may be substituted. The substituent groups which may be
possessed by the "C.sub.6-14 aryl", "C.sub.7-16 aralkyl" or "heterocyclic
group" are similar to those mentioned for the "benzene ring which may be
substituted".
Preferred are
##STR31##
and so on. In the above formulas, G is as defined hereinbefore.
(iv)
##STR32##
wherein ring D represents an aromatic ring which may be substituted, Y
represents --CH.sub.2 --, --CO-- or --CH(OH)--, s and t each represents an
integer of 1 to 3.
The "aromatic ring" for the ring D is (a) a benzene ring or (b) 5- or
6-membered heteroaromatic ring having 1 to 3 hetero-atoms selected from
nitrogen, oxygen and sulfur in addition to carbon as ring members, such as
the following, among others.
##STR33##
The substituent groups which may be possessed by the "aromatic ring" are
similar to those mentioned for the "benzene ring which may be
substituted".
Preferably,
##STR34##
wherein ring D.sup.a represents a benzene ring which may be substituted;
Y.sup.a represents --CH.sub.2 or --CO--, among others, is used.
A still more preferred example is
##STR35##
wherein G is as defined hereinbefore.
In the following disclosure in this specification, (i) the halogen may for
example be fluorine or chlorine; (ii) C.sub.1-6 alkyl which may be
halogenated may for example be methyl, ethyl, isopropyl or
trifluoromethyl; (iii) C.sub.1-6 alkyl may for example be methyl, ethyl or
isopropyl; (iv) C.sub.1-6 alkoxy which may be halogenated may for example
be methoxy, ethoxy, isopropoxy or trifluoromethoxy; (v) C.sub.1-6 alkoxy
may for example be methoxy, ethoxy or isopropoxy; (vi) C.sub.1-6 alkylthio
which may be halogenated may for example be methylthio, ethylthio or
isopropylthio; (vii) mono(C.sub.1-6)alkylamino may for example be
methylamino or ethylamino; (viii) di(C.sub.1-6)alkylamino may for example
be dimethylamino or diethylamino; (ix) C.sub.1-6 alkoxycarbonyl may for
example be methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl; and (x)
C.sub.1-7 acylamino may for example be formylamino, acetylamino or
propionylamino.
In the above formula, ring A represents a benzene ring which may be
substituted.
Preferred is a benzene ring which may be substituted by 1 to 3 substituent
groups selected from halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy, among
others. More preferred is an unsubstituted benzene ring.
In the above formula, Ar represents an aromatic group which may be
substituted.
Preferred is a phenyl group which may be substituted by 1 to 3 substituents
selected from halogen atom, C.sub.1-6 alkyl which may be substituted,
C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may
be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino.
Still more preferred is a phenyl group which may be substituted by one
halogen atom. Specially, an unsubstituted phenyl group is preferred.
Referring, further, to the above formula, R.sup.1 and R.sup.2 independently
represent hydrogen atom, acyl group or a hydrocarbon group which may be
substituted; or R.sup.1 and R.sup.2 taken together with the adjacent
nitrogen atom form a nitrogen-containing heterocyclic group.
The preferred combination of R.sup.1 and R.sup.2, where they do not form a
ring, is as follows: R.sup.1 is hydrogen and R.sup.2 is C.sub.7-16 aralkyl
(e.g. benzyl, phenethyl, etc.) which may be substituted by 1 to 3
substituent groups selected from among halogen, C.sub.1-6 alkoxy which may
be halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and acylamino.
The still more preferred combination is that R.sup.1 is hydrogen and
R.sup.2 is C.sub.7-16 aralkyl (e.g. benzyl, phenethyl, etc.) which may be
substituted by one substituent group selected from halogen, C.sub.1-6
alkyl, C.sub.1-6 alkoxy and C.sub.1-6 alkoxycarbonyl.
The preferred examples of the ring which may be formed by R.sup.1 and
R.sup.2 taken together with the adjacent nitrogen atom are as follows.
(1)
##STR36##
wherein Z represents oxygen, >CH--W or >N--W in which W represents (a)
hydrogen or (b) a C.sub.6-14 aryl (e.g. phenyl) or C.sub.7-16 aralkyl
(e.g. benzyl) group which may be substituted by 1 to 3 substituent groups
selected from halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6
alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be
halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino, or
(2)
##STR37##
wherein ring D represents (a) a benzene ring or (b) 5- or 6-membered
heteroaromatic ring which may be substituted by 1 to 3 hetero-atoms
selected from nitrogen, oxygen and sulfur in addition to carbon as ring
members (e.g. thiophene, pyridine, etc.) which may be substituted by 1 to
3 substituent groups selected from halogen, C.sub.1-6 alkyl which may be
halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino, Y represents --CH.sub.2 --, --CO--
or --CH(OH)--, s and t each represents an integer of 1 to 3.
the more preferred examples are (1)
##STR38##
wherein W represents a C.sub.6-14 aryl (e.g. phenyl) or C.sub.7-16 aralkyl
(e.g. benzyl) group which may be substituted by 1 to 3 substituent groups
selected from halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6
alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be
halogenated, nitro, cyano, sulfo, hydroxy, amino, mono
(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino, and
(2)
##STR39##
wherein ring D.sup.a represents a benzene ring which may be substituted by
1 to 3 substituent groups selected from among halogen, C.sub.1-6 alkyl
which may be halogenated, C.sub.1-6 alkoxy which may be halogenated,
C.sub.1-6 alkylthio which may be halogenated, nitro, cyano, sulfo,
hydroxy, amino, mono(C.sub.1-6)-alkylamino, di(C.sub.1-6)alkylamino,
carboxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-7 acylamino, Y.sup.a
represents --CH.sub.2 -- or --CO--.
In the above formulae, m represents an integer of to 6 and is preferably is
3.
Further in the above formulae, n represents an integer of 1 to 3 and is
preferable is 1.
In the above formulae, ----- represents a single bond or a double bond.
Where X in the above formulae stands for --O-- or --NR.sup.3 -- wherein
R.sup.3 is hydrogen, acyl or hydrocarbon group 3 which may be substituted
where ----- is a single bond, and X stands for .dbd.N-- where ----- is a
double bond.
The "acyl" and "hydrocarbon group which may be substituted" for R.sup.3 are
both as defined hereinbefore. R.sup.3 is preferably hydrogen or a
C.sub.1-6 alkyl group.
Preferably, in the above formula, ----- represents a single bond and X
represents --O--.
It is also preferable that, in the above formulae, ----- represents a
single bond and X represents --NR.sup.3a -- wherein R.sup.3a is hydrogen
or C.sub.1-6 alkyl.
The preferred compounds of this invention are:
(1) compounds of the following formula
##STR40##
wherein ring A represents a benzene ring which may be substituted by 1 to
3 substituent groups selected from halogen, C.sub.1-6 alkyl which may be
halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino,
Ar.sup.a represents phenyl which may be substituted by 1 to 3 substituent
groups selected from halogen, C.sub.1-6 alkyl which may be halogenated,
C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may
be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino,
W represents a C.sub.6-14 aryl (e.g. phenyl) or C.sub.7-16 aralkyl (e.g.
benzyl) group which may be substituted by 1 to 3 substituent groups
selected from halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6
alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be
halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino,
m represents an integer of 1 to 6,
----- represents a single bond,
X.sup.a stands for --O-- or --NR.sup.3a -- wherein R.sup.3a is hydrogen or
C.sub.1-6 alkyl, or a salt thereof.
(2) Compounds of the formula
##STR41##
wherein ring A represents a benzene ring which may be substituted by 1 to
3 substituent groups selected from halogen, C.sub.1-6 alkyl which may be
halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino,
Ar.sup.a represents phenyl which may be substituted by 1 to 3 substituent
groups selected from halogen, C.sub.1-6 alkyl which may be halogenated,
C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may
be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino,
ring D.sup.a represents a benzene ring which may be substituted by 1 to 3
substituent groups selected from halogen, C.sub.1-6 alkyl which may be
halogenated, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, nitro, cyano, sulfo, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, carboxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-7 acylamino,
Y.sup.a represents --CH.sub.2 -- or --CO--,
m represents an integer of 1 to 6,
----- represents a single bond,
X.sup.a stands for --O-- or --NR.sup.3a -- wherein R.sup.3a is hydrogen or
C.sub.1-6 alkyl, or a salt thereof.
The following is a partial listing of preferred species of the compound of
this invention. These compounds have excellent GnRH receptor antagonizing
activity.
N,N-Diphenyl-(3-[3-(4-phenylisochroman-4-yl)propyl]amino)propionamide
hydrochloride;
N-(2-Phenoxyethyl)-3-[3-(4-phenylisochroman-4-yl)propylaminomethyl]benzamid
e hydrochloride;
(3)
3,4-Dihydro-6,7-dimethoxy-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[naph
thalene(1(1H),2'-piperidine] hydrochloride;
(4) Methyl 3-[3-(4-phenylisochroman-4-yl)propylaminomethyl]benzoate
hydrochloride;
(5) 4-[3-(3-Methylbenzylamino)propyl]-4-phenylisochroman hydrochloride;
(6)
3,4-Dihydro-1'-[3-(4-phenylisochroman-4yl)propyl]spiro[benzo[b]thiophen-5(
4H)-4-one,2'-piperidine]hydrochloride;
(7)
3,4-Dihydro-6-methoxy-1'-[3-(4-phenylisochroman-4yl)propyl]spiro[naphthale
n-2(1H)-1-one,2'-piperidine]hydrochloride;
(8)
3,4-Dihydro-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[naphthalen-2(1H)-1
-one,2'-piperidine]hydrochloride;
(9)
3,4-Dihydro-6,7-dimethoxy-1'-[3-(4-[fluorophenyl]-isochroman-4-yl)propyl]s
piro[naphthalene-2(1H),2'-piperidine]hydrochloride;
(10)
4-[3-(1,2,3,4-Tetrahydronaphthalen-1-yl)aminopropyl]-4-phenylisochroman hy
drochloride;
(11)
3,4-Dihydro-1'-[3-(4-[phenylisochroman-4yl)propyl]spiro[naphthalene-2(1H),
2'-piperidine] hydrochloride
(12) 4-(3-phenethylaminopropyl)-4-phenylisochroman hydrochloride;
(13)
3,4-Dihydro-6-methoxy-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[naphthal
ene-2(1H),2'-piperidine]hydrochloride; and
(14)
3,4-Dihydro-6,7-dimethoxy-1'-[4-(4-phenylisochroman-4-yl)butyl]spiro[napht
halene-2(1H),2'-piperidine] hydrochloride.
Furthermore, the following is a partial listing of the preferred compounds,
which have excellent calcium antagonizing or monoamine-uptake inhibiting
activities of this, invention.
(1)
3,4-Dihydro-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[naphthalene-2(1H),
2'-piperidine] hydrochloride,
(2)
3,4-Dihydro-1'-[2-(4-phenylisochroman-4-yl)ethyl]spiro[naphthalene-2(1H),2
'-piperidine] hydrochloride,
(3) 4-[2-(4-Benzylpiperazin-1-yl)ethyl]-4-phenylisochroman dihydrochloride,
(4) 4-{3-[4-(p-Fluorophenyl)piperazin-1-yl]propyl}-4-phenylisochroman
dihydrochloride,
(5) 4-[3-Benzylamino)propyl]-4-phenylisochroman hydrochloride,
(6)
3,4-Dihydro-6-methoxy-1'-[3-(4-phenylisochroman4-yl)propyl]spiro[naphthale
ne-2(1H),2'-piperidine] hydrochloride,
(7) 4-[3-(4-phenylpiperidino)propyl]-4-phenylisochroman hydrochloride,
(8) 4-[3-(.beta.-phenethylamino)propyl]-4-phenylisochroman hydrochloride,
(9) 4-[3-(o-Fluorobenzylamino)propyl]-4-phenylisochroman hydrochloride,
(10) 4-[3-(o-Chlorobenzylamino)propyl]-4phenylisochroman hydrochloride,
(11) 4-[3-(3,4-Dimethoxyphenethylamino)propyl]-4-phenylisochroman
hydrochloride,
(12) 4-[3-(2-Picolylamino)propyl]-4-phenylisochroman dihydrochloride,
(13) 4-[3-(1-Hexamethyleneimino)propyl]-4-phenylisochroman hydrochloride,
(14)
4-(p-Chlorophenyl)-3,4-dihydro-4-[3-(4-phenylpiperazin-1-yl)propyl]isoquin
oline trihydrochloride,
(15) 3,4-Dihydro-4-phenyl-4-[3-(4-phenylpiperazin-1-yl)propyl]isoquinoline
dihydrochloride,
(16) 4-[3-(N-Benzyl-N-methyl)aminopropyl]-3,4-dihydro-4-phenylisoquinoline
dihydrochloride,
(17)
4-{3-[4-(p-Fluorophenyl)piperazin-1-yl]propyl}-1,2,3,4-tetrahydro-4-phenyl
-isoquinoline dihydrochloride,
(18)
4-[3-(N-Benzyl-N-methyl)aminopropyl]-4-phenyl-1,2,3,4-tetrahydroisoquinoli
ne dihydrochloride,
(19)
1,2,3,4-Tetrahydro-4-phenyl-4-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,3,4te
trahydroisoquinoline trihydrochloride,
(20)
1,2,3,4-Tetrahydro-2-methyl-4-phenyl-4-[3-(4-phenylpiperazin-1-yl)propyl]i
soquinoline trihydrochloride,
(21)
1,2,3,4-Tetrahydro-4-{2-[4-(p-fluorophenyl)piperidino]ethyl}-2-(3-methoxyp
henylaminocarbonyl)-4-phenylisoquinoline,
(22)
4-(p-Chlorophenyl)-2-methyl-4-[3-(4-phenylpiperidino)propyl]-1,2,3,4-tetra
hydroisoquinoline dihydrochloride, and
(23)
4-[3-(N-Benzyl-N-methylamino)propyl]-4-phenyl-2-phenylcarbamoyl-1,2,3,4-te
trahydroisoquinoline hydrochloride.
The preferred salts of compound (I) of this invention include medicinally
acceptable acid addition salts. Among such salts are salts with inorganic
acids, such as hydrochloride, hydrobromide, hydroiodide, sulfate,
phosphate, etc., and salts with organic acids, such as acetate, oxalate,
succinate, ascorbate, maleate, lactate, citrate, tartrate,
methanesulfonate, benzoate and so on.
Among species of the compound of this invention are optically active
compounds and, of course, the respective isomers available on optical
resolution fall within the scope of this invention.
Such optical isomers can be obtained by the per se known technology, e.g.
by using an optically active synthetic intermediate or subjecting the
final racemic compound to optical resolution in the conventional manner,
The technology that can be used for the optical resolution includes a
method which comprises preparing a salt with an optically active acid and
separating the salt by fractional recrystallization; a method which
comprises subjecting the racemic compound or salt to chromatography using
a optically active column (chiral column), for example ENANTIO-OVM (Toso),
and eluting the desired isomer with a solvent or solvents selected from
among water, various buffer solutions (e.g. phosphate buffer), and organic
solvents such as alcoholic solvents (e.g. methanol, ethanol, etc.),
nitrile solvents (e.g. acetonitrile), hexane, ethyl ether, etc.; and a
method which comprises causing the racemic mixture to condense with an
optically active organic acid, for example MPTA
[.alpha.-methoxy-.alpha.-(trifluoromethyl)phenylacetic acid] or
menthoxyacetic acid by a conventional technique such as the acid chloride
process to provide a mixture of diastereomers of the amide, fractionating
it by a fractional purification technique such as fractional
recrystallization or silica gel chromatography, and subjecting it to acid
or basic hydrolysis.
While the compound (I) or salt of this invention can be produced by various
alternative processes, the processes described hereinafter can be
mentioned as typical examples.
The compound (I) of this invention, where it is a free compound, can be
converted to a salt by a conventional technique and, where it is a salt,
can be converted to the free compound by a conventional technique. The
compound (I) or salt thus produced can be isolated and purified by known
procedures such as solvent extraction, pH adjustment, redistribution,
crystallization, recrystallization and chromatography. Where the compound
(I) or salt is optically active, the isomers can be fractionally isolated
by the optical resolution techniques described hereinbefore.
The "leaving group" for L is a functional group which is easily displaced
by chemical reaction, thus including but being not limited to halogen,
methanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy and
trifluoromethanesulfonyloxy.
The specific solvents that can be used for the above reactions are as
follows.
The "ether solvent" includes tetrahydrofuran, ethyl ether, dioxane,
isopropyl ether, 1,2-dimethoxyethane and so on;
The "halogenated hydrocarbon solvent" includes dichloromethane,
1,2-dichloroethane, chloroform, carbon tetrachloride and so on.
The "aromatic hydrocarbon solvent" includes benzene, toluene, xylene and so
on.
The "alcoholic solvent" includes methanol, ethanol, isopropyl alcohol,
tert-butanol, ethylene glycol, sec-butanol and so on.
<Production Process 1> Synthesis of an Isochroman-form Derivative
The compound (I) wherein X is an oxygen atom can be synthesized by the
following process.
[Step 1] Synthesis of diol derivative (5) (cf. the flow chart of the
production process 1 hereinafter)
A substituted phenylacetonitrile derivative (1) is reacted with an acrylic
ester (e.g. methyl acrylate or ethyl acrylate) or
L--(CH.sub.2).sub.m-1 --CO.sub.2 --J
wherein L represents a leaving group; J represents lower (C.sub.1-6) alkyl,
such as methyl or ethyl, in an inert solvent or mixed solvent, e.g. an
ether solvent, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
acetonitrile, an alcoholic solvent and/or an aromatic hydrocarbon solvent
in the presence of a base at -20.degree. C. to 120.degree. C. for 5
minutes to 18 hours to provide an ester derivative (2).
The base that can be used includes strong bases such as sodium hydroxide,
potassium t-butoxide, lithium diisopropylamide, etc., inorganic bases such
as alkali metal or alkaline earch metal hydroxides, carbonates or
bicarbonates, e.g. sodium hydroxide, potassium carbonate, etc., and
organic bases such as triethylamine, DBU
(1,8-diazabicyclo[5,4,0]-7-undecene) and so on.
Particularly in the reaction with an acrylic ester, the objective
derivative can be produced by conducting the reaction with 1 to 5
equivalents of the acrylic ester in an alcohol, e.g. ethanol, in the
presence of a catalyst amount to 5 equivalents of DBU under heating at
40.degree. C. to 100.degree. C. and stirring for 1 to 3 hours.
Where a bromoacetic ester is used, the objective derivative can be produced
by conducting the reaction in an ether solvent, e.g. tetrahydrofuran (THF)
in the presence of 1 to 3 equivalents of a strong base, e.g. sodium
hydride, at 0.degree. C. to 20.degree. C. for 5 minutes to 20 hours.
The ester derivative (2) can be converted to the diol compound by a
combination of reduction and acid hydrolysis. Thus, using not less than 3
equivalents of a metal hydride (e.g. lithium aluminum hydride,
diisobutylaluminum hydride, diborane, etc.) in a solvent, such as an ether
solvent (e.g. THF, ethyl ether, etc.) or an aromatic hydrocarbon solvent
(e.g. toluene), the ester residue is reduced to hydroxymethyl and, at the
same time, the cyano group is reduced to iminoalcohol (3). When lithium
aluminum hydride, for instance, is employed, the reaction temperature is
preferably 0.degree. C. to 20.degree. C. and the reaction time 0.5 to 2
hours.
The resulting iminoalcohol (3) is subjected, without purification, to acid
hydrolysis and further to reduction, whereby it is converted to the diol
(5). The acid hydrolysis of iminoalcohol (3) can be accomplished by
heating and stirring the imminoalcohol in a solvent mixture of water and
either an inorganic acid, e.g. hydrochloric acid, sulfuric acid or the
like, or an organic acid such as acetic acid, trifluoroacetic acid or the
like at 20.degree. C. to 100.degree. C. for 30 minutes to 25 hours.
Preferably, (3) is treated in 2N-hydrochloric acid under heating at
50.degree. C. and stirring for 5 to 24 hours.
The reduction reaction mentioned above can be the ordinary reduction
reaction using a metal hydride which is preferably lithium aluminum
hydride or sodium borohydride. In the case of lithium aluminum hydride,
the reaction is carried out in an ether solvent at 0.degree. C. to
30.degree. C. for 30 minutes to 2 hours.
On the other hand, the diol compound can also be obtained with ease by
reducing the .gamma.-butyrolactone compound (6) with, for example, a metal
hydride. This reduction can be accomplished by the technique described in
detail by Richard C. Larock's Comprehensive Organic Transformation.
Taking .alpha.,.alpha.-diphenyl-.gamma.-lactone (m=2) as an example, the
corresponding diol compound (5) can be obtained in good yield by treating
the lactone with 2 to 10 equivalents of lithium aluminum hydride in an
ether solvent (e.g. THF, ethyl ether) at -20.degree. C. to 50.degree. C.
for 0.5 to 5 hours.
[Step 2] Construction of the Isochroman Nucleus
Cyclization of the diol (5) can be achieved by using formalin or a
formaldehyde polymer, e.g. paraformaldehyde, in the presence of an organic
acid, e.g. trifluoroacetic acid or methanesulfonic acid, or an inorganic
acid, e.g. sulfuric acid, optionally in an inert solvent such as a
halogenated hydrocarbon solvent (e.g. dichloromethane, dichloroethane,
etc.) and conducting the reaction at 10.degree. C. to 100.degree. C. for
10 minutes to 18 hours. The formaldehyde polymer may be used in excess and
is preferably used in a proportion of 1 to 10 equivalents.
[Step 3] Introduction of
##STR42##
The hydroxyl group of isochroman derivative (7) can be easily converted to
a leaving group [Compound (8)]. The preferred leaving group is tosyloxy or
halogen, e.g. bromine, iodine or the like. This conversion reaction can be
carried out by the per se known technique (e.g. the techniques described
in Comprehensive Organic Transformation referred to above). For example,
the conversion to tosyloxy can be achieved by reacting (7) with
p-toluenesulfonyl chloride (1 to 2 equivalents) in the presence of an
organic base (1 to 5 equivalents), e.g. triethylamine, in a halogenated
hydrocarbon solvent (e.g. dichloroethane, dichloromethane, etc.) at
0.degree. C. to 30.degree. C. The iodo-compound can be obtained by
reacting the tosyl compound with sodium iodide (1 to 5 equivalents) in an
inert solvent. Preferably the reaction temperature is 10.degree. C. to
60.degree. C. and the reaction time is 10 minutes to 5 hours. The
particularly preferred inert solvent is acetone, methyl ethyl ketone or
the like.
The objective compound of this invention can be synthesized by using the
corresponding amine
##STR43##
and conducting the reaction in the absence or presence of an inert solvent
(e.g. acetonitrile, DMF, acetone or an alcoholic solvent) at 10.degree. C.
to 100.degree. C. for 1 to 24 hours. The preferred proportion of
HN-R.sup.1 R.sup.2 is 1 to 3 equivalents and this reaction can be
conducted smoothly in the presence of an inorganic base, e.g. potassium
carbonate, or an organic amine, e.g. triethylamine. While the type and
amount of the base may vary with different amines, the base is preferably
used in a proportion of 2 to 4 equivalents.
Production Process 1
##STR44##
<Production process 2> Synthesis of an Isoquinoline-form Derivative
The compound in which X represents --NR.sup.3 -- or a nitrogen atom can be
synthesized by the following process.
[Step 4] Synthesis of Aminoalcohol (10)
The aminoalcohol (10) can be obtained by subjecting the cyano ester (2)
obtained in the course of Step 1 to direct reduction or the iminoalcohol
(3) to reduction reaction.
In the process for direct reduction of cyano ester (2), the cyano ester
derivative (2) is treated with not less than 4 equivalents of a metal
hydride (e.g. lithium aluminum hydride, diisobutylaluminum hydride,
diborane, sodium borohydride, etc.), optionally in the presence of
aluminum chloride, cobalt chloride or the like, in an ether solvent (e.g.
THF, ethyl ether, etc.) or an aromatic hydrocarbon solvent (e.g. toluene).
When lithium aluminum hydride (4 to 10 equivalents) is used, the reaction
temperature is preferably 20.degree. C. to 80.degree. C. and the reaction
time is preferably 0.5 to 12 hours.
The same reaction conditions can be applied to the reduction of
iminoalcohol (10).
[Step 5] Formylation of the Amino Group and Introduction of
##STR45##
The amino group of the aminoalcohol (10) is selectively formylated by
treating (10) with a formic acid-lower fatty acid anhydride system and
subsequent basification to obtain compound (11). This formylation reaction
proceeds easily as the starting compound (10) is dissolved in an excess (3
to 10 equivalents) of formic acid and 1 to 1.5 equivalents of a fatty acid
anhydride and stirred at 0.degree. C. to 30.degree. C. for 1 to 24 hours.
In the subsequent basification step, the product is dissolved in an
alcoholic solvent and stirred together with, for example, an alkali metal
or alkaline earth metal hydroxide (1 to 5 equivalents) at 0.degree. C. to
40.degree. C. for 0 minutes to 5 hours. This procedure gives the formamide
(11).
The conversion of hydroxyll to a leaving group and the introduction of
##STR46##
can be carried out as described in Step 3.
[Step 6] Formation of the Insoquinolene Ring
Formation of the isoquinoline ring can be accompolished by acid catalysis
reaction. While a variety of acid catalysts can be used, polyphosphoric
acid is particularly preferred.
Thus, the formamide (13) and an excess (5 to 100 equivalents) of
polyphosphoric acid are heated together at 100.degree. C. to 200.degree.
C. with stirriing for 1 to 5 hours, whereby the dihydroisoquinoline
compound (14) is obtained.
The conversion to the tetrahydroisoquinoline compound (15) can be achieved
by the per se known reduction reaction (e.g. the process using a metal
hydride or the catalytic reduction using a metal catalyst).
The reduction reaction using a metal hydride cab be achieved by stirring
the starting compound together with lithium aluminum hydride, sodium
borohydride, diborane, lithium borohydride or the like (1.about.10
equivalents) in an alcoholic solvent or an ether solvent at -20.degree. C.
to 40.degree. C. for 5 minutes to 5 hours.
Where a catalytic reduction process using a metal catalyst is adopted, the
reduction can be conducted using Raney nickel, platinum oxide, palladium
metal, palladium-on-carbon or the like in an alconolic solvent or an ether
solvent at 10.degree. C. to 100.degree. C. and a hydrogen pressure of not
less than 1 atmosphere for 1 to 18 hours. The preferred hydrogen pressure
is 1 to 10 atmospheres.
[Step 7]
Introduction of substituent group R.sup.3 to the ring nitrogen atom of
tetrahydroisoquinoline derivative (15) can be achieved by the per se known
methods.
The introduction of an alkyl group, for instance, can be achieved by using
an alkyl halide or by reductive alkylation using an alkylaldehyde.
Taking reductive alkylation as an example, the reaction can be accomplished
by using an excess (1 to 10 equivalents) of formalin or an alkylaldehyde
(1 to 10 equivalents) in an alcoholic solvent in the presence of Raney
nickel, platinum oxide, palladium metal, palladium-on-carbon or the like
at 10.degree. C. to 100.degree. C. and a hydrogen pressure of not less
than 1 atmosphere for 1 to 18 hours. The preferred range of hydrogen
pressure is 1 to 10 atmospheres.
Referring to the reaction with an alkyl halide, the alkyl compound can be
synthesized using an alkali metal or alkaline earth metal hydroxide,
carbonate or bicarbonate (e.g. potassium carbonate, sodium carbonate,
sodium hydroxide, potassium hydroxide, etc.) or a strong base (e.g. sodium
hydride, lithium hydride, etc.) in acetonitrile, DMF and/or an ether
solvent at a temperature of 10.degree. to 100.degree. C. for 1 to 100
hours.
In the case of acylation or carbamoylation, the reaction with the
corresponding isocyanate or acyl chloride is conducted in a halogenated
hydrocarbon solvent (e.g. dichlomethane, dichloroethane, chloroform, etc.)
at a reaction temperature of -20.degree. C. to 50.degree. C. for 5 minutes
to 24 hours. This reaction may be conducted in the presence of an organic
base, e.g. triethylamine, or an inorganic base, e.g. an alkali metal or
alkaline earth metal hydroxide, carbonate or bicarbonate (e.g. potassium
carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, etc.)
(a catalyst amount to 10 equivalents).
For the functional transformation or modification of
##STR47##
various per se known reactions such as oxidation, reduction, alkylation
and acylation can be carried out in combination to provide other
derivatives.
<Production process 2>
##STR48##
The various starting compounds and salts for the objective compound (I) of
this invention can be respectively isolated and purified by known
procedures such as solvent extraction, pH adjustment, redistribution,
salting-out, crystallization, recrystallization and chromatography but
each reaction mixture containing the corresponding compound or salt may be
directly submitted to the next reaction step.
In the respective reactions according to the invention and the respective
reactions for synthesizing the starting or intermediate compounds, where
any of such compounds has an amino, carboxyl and/or hydroxy group, such
groups may be previously protected with an appropriate protective group
that is commonly used in peptide or other chemistry and the objective
compound can be ultimately obtained by removing the protective group as
required.
The protective group that can be used for protection of the amino group
includes but is not limited to C.sub.1-6 alkyl-carbonyl (e.g. formyl,
acetyl, ethylcarbonyl, etc.), C.sub.1-6 alkyloxycabonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, etc.), benzoyl, C.sub.7-10
arakyl-carbonyl (e.g. benzylcarbonyl etc.), trityl, phthaloyl and,
N,N-dimethylaminomethylene. These groups may respectively have 1-3
substituents, e.g. halogen (e.g. fluorine, chlorine, bromine, iodine), and
nitro.
The protective group that can be used for protection of the carboxyl
function includes but is not limited to C.sub.1-6 alkyl (e.g. methyl,
ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl and
silyl. These groups may respectively have 1-3 substituent groups such as
halogen (e.g. fluorine, chlorine, bromine and iodine), C.sub.1-6
alkyl-carbonyl (e.g. formyl, acetyl, ethylcarbonyl, butylcarbonyl, etc.)
and nitro.
The protective group that can be used for protection of the hydroxy
function includes but is not limited to C.sub.1-6 alkyl (e.g. methyl,
ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C.sub.7-10
aralkyl (e.g. benzyl), C.sub.1-6 alkyl-carbonyl (e.g. formyl, acetyl,
ethylcarbonyl, etc.), benzoyl, C.sub.7-10 aralkylcarbonyl (e.g.
benzylcarbonyl etc.), tetrahydropyranyl, tetrahydrofuranyl and silyl.
These groups may respectively have 1-3 substituent groups such as halogen
(e.g. fluorine, chlorine, bromine and iodine), C.sub.1-6 alkyl (e.g.
methyl, ethyl, n-propyl, etc.), phenyl, C.sub.7-10 aralkyl (e.g. benzyl)
and nitro.
While these protective groups can be removed by various methods known per
se or analogous therewith, the procedures using an acid, a base,
ultraviolet light, hydrazine, phenylhydrazine, sodium
N-methyldithiocarbamate, tetrabutylammonium fluoride and palladium
acetate, respectively, can be selectively utilized.
The compound (I) or its pharmaceutically acceptable salt of this invention,
on administration to man and other mammalian animals (e.g. mouse, rat,
rabbit, dog, bovine, swine, etc.), inhibits secretion of gonadotropin to
modulate blood steroid hormone levels, thanks to its GnRH receptor
antagonizing activity, so that it can be safely used for the ovulation
inhibitor, prevention agent for implantation of the ovum or the
prophylactic and therapeutic agent for various diseases such as
amenorrhea, prostatic cancer, prostatic hypertrophy, endometriosis,
hysteromyoma, breast cancer, acne, precocious puberty, premenstrual
syndrome, polycystic ovary syndrome, pituitary tumor and hyperandrogenism
in humans.
The compound (I) or its pharmaceutically acceptable salt of this invention
can be safely used for a contaceptive for female or male, an
ovulation-inducing agent for female, an estrus regulator in animals, an
improvement of quality of the edible meats, a growth promotor in animals
or an oviposition promotor in fish.
The compound (I) or its pharmaceutically acceptable salt of this invention
can be effectively used together with a sterolidal or non-stroidal
antiandrogen agent.
The compound (I) and pharmaceutically acceptable salt of this invention
have activity to antagonize monoamines uptake by synapses and an excessive
calcium ion influx into neurons in man and other mammalian animals (e.g.
mouse, rat, rabbit, dog, cattle, swine, etc.) and can be used safely in
the prevention and treatment of various diseases inclusive of emotional
disturbances such as depression, anxiety, alcohol dependence, appetite
disorder, panic attack, obsession syndrome, etc., neurodegenerative
diseases such as Parkinson's disease, Alzheimer's disease, etc., epilepsy,
convulsion, and cerebrovascular disorders such as cerebral apoplexy,
cerebral infarction, etc. particularly in humans.
The compound (I) or salt of this invention features a low toxic potential
and a low risk of side effect. The oral acute toxicity (LD.sub.50) of the
compound in rats is not less than 100 mg/kg.
The compound (I) or salt of this invention can be safely administered
orally or otherwise in its neat form or in the form of a pharmaceutical
composition which can be prepared by the per se known pharmaceutical
technology using medicinally acceptable carriers, for example tablets
(inclusive of dragees, film-coated tablets, etc.), powders, granules,
capsules (inclusive of soft capsules), elixirs, injections, suppositories,
controlled-release tablets and other drug delivery systems. The dosage
depends on the subject, route of administration, type of disease and other
factors. However, taking the oral treatment of cerebral apoplexy as an
example, the recommended daily dosage for an average adult (b. w. 60 kg)
is 0.1 to 500 mg, preferably 10 to 100 mg, which dosage can be
administered in a single dose or in a few divided doses daily.
The pharmaceutically acceptable carrier that can be used includes those
organic and inorganic carriers which are commonly used in the
pharmaceutical field, including excipients, lubricants, binders,
disintegrators, etc. for solid compositions and solvents, solubilizers,
suspending agents, isotonizing agents, buffers, local anesthetics, etc.
for liquid compositions. Where necessary, various additives such as
preservatives, antioxidants, coloring agents, sweeteners, etc. can also be
employed. The preferred excipient includes lactose, sucrose, D-mannitol,
starch, crystalline cellulose, light silicic anhydride, etc. The preferred
lubricant includes magnesium stearate, calcium stearate, talc and
colloidal silica, among others. The preferred binder includes crystalline
cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose,
hydroxypropylmethylcellulose and polyvinylpyrrolidone, among others. The
preferred disintegrator includes starch, carboxymethylcellulose,
carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch
sodium and so on. The preferred solvent includes water for injection,
alcohols, propylene glycol, macrogols, sesame oil and corn oil, among
others. The preferred solubilizer includes but is not limited to
polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate,
ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate
and sodium citrate. The preferred suspending agent includes various
surfactants such as stearyltriethanolamine, sodium lauryl sulfate,
laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium
chloride, glyceryl monostearate, etc. and various hydrophilic
macromolecular substances such as polyvinyl alcohol, polyvinylpyrrolidone,
carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose and so on. The preferred
isotonizing agent includes but is not limited to sodium chloride, glycerin
and D-mannitol. The preferred buffer includes phosphate, acetate,
carbonate and citrate buffer solutions, among others. The preferred local
anesthetic includes benzyl alcohol, among others. The preferred
preservative includes but is not limited to p-hydroxybenzoic acid esters,
chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,
sorbic acid and so on. The preferred antioxidant includes sulfites,
ascorbic acid and so on.
The compound (I) or salt of this invention, thanks to its GnRH receptor
antagonizing activity, inhibits secretion of gonadotropin in mammals to
control blood steroidal sex hormone levels and, particularly in man, can
display efficacy in the prophylaxis and therapy of various diseases.
Typical examples of its application are inhibition of ovulation or of
implantation of the ovum in mammalian animals and the prevention and
treatment of amenorrhea, prostatic cancer, prostatic hypertrophy,
endometriosis, breast cancer, acne, premature puberty, premenstrual
syndrome, polycystic ovary syndrome and hyperandrogenism.
In addition, the compound (I) or salt of this invention is useful for the
improvement of meat quality.
The GnRH receptor antagonist composition of this invention, when used in
combination with a GnRH receptor agonist in mammalian animals,
particularly female animals, enables the endogenic gonadotropin level to
be controlled and maintained at the proper level and can provide an
effective therapeutic modality for induction of ovulation.
The objective compound (I) and salt of this invention have also activity to
antagonize the synaptic uptake of monoamines such as norepinephrine (NE)
and serotonine (5-HT) and the excessive influx of calcium ion and,
therefore, can be safely used in the prevention and treatment of various
diseases inclusive of emotional disturbances such as depression, anxiety,
alcohol dependence, appetite disorder, panic stroke, obsession syndrome,
etc., neurodegenerative diseases such as Parkinson's disease, Alzheimer's
disease, etc., epilepsy, convulsion, and cerebrovascular disorders such as
cerebral apoplexy, cerebral infarction, etc. and brain damage due to a
traffic accident particularly in humans.
The following reference examples, examples and experimental examples are
intended to describe this invention in further detail. It should be
understood that these examples are merely illustrative and by no means
limitative of the invention and that many changes and modifications can be
made without departing from the spirit and scope of the invention.
The term "room temperature" as used in the following reference examples and
examples means the range of 0.degree.-30.degree. C. The meanings of the
various symbols used are as follows.
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: coupling constant
Hz: Herz
CDCl.sub.3 : deuterochloroform
THF: tetrahydrofuran
DMF: N,N-dimethylformamide
DMSO: dimethyl sulfoxide
.sup.1 H-NMR: proton nuclear magnetic resonance spectrum (NMR spectra was
measured by the free form.)
REFERENCE EXAMPLE 1-1
2-(p-Fluorophenyl)-2-phenylacetonitrile
A solution of p-fluoromandelonitrile (45 g) in benzene (90 g) was added
portionwiste to sulfuric acid (85 ml) with constant stirring at
5.degree.-10.degree. C. After completion of portionwise addition, the
mixture was further stirred for 30 minutes. The reaction mixture was then
diluted with water (500 ml) and extracted with ethyl acetate (300
ml.times.2). The extract was washed with water, dried over anhydrous
sodium sulfate and concentrated to provide a colorless oil (59.5 g).
Using the corresponding mandelonitrile derivative and chlorobenzene, the
following compounds 1-2 and 1-3 were respectively synthesized in otherwise
the same manner as Reference Example 1-1.
Compound 1-2
2-(p-Chlorophenyl)-2-phenylacetonitrile
Compound 1-3
Bis(p-chlorophenyl)acetonitrile
The structural formulas, physical properties and NMR spectra of the above
compounds are shown in Table 1.
TABLE 1
______________________________________
##STR49##
Re-
ference
Example
R.sup.0
Ar .sup.1 HNMR (.delta..sub.ppm,
______________________________________
CDCl.sub.3)
1-1 H
##STR50## 5.13(1H, s), 7.00-7.50(9H, m)
1-2 H
##STR51## 5.11(1H, s), 7.23-7.42(9H, m)
1-3 p-Cl
##STR52## 5.10(1H, s), 7.20-4.20(8H, m)
______________________________________
REFERENCE EXAMPLE 2-1
Ethyl 3-cyano-3,3-diphenylpropionate
To a solution of diphenylacetonitrile (1 g) in tetrahydrofuran (10 ml) was
added 60% sodium hydride (0.25 g) portionwise under ice-cooling and
stirring. After completion of portionwise addition, the mixture was
further stirred for 15 minutes. Then, ethyl bromoacetate (0.69 ml) was
added dropwise and the mixture was further stirred for 30 minutes. The
reaction mixture was then diluted with water and the organic layer was
extracted with ethyl acetate. The extract was washed with water, dried
over anhydrous sodium sulfate and concentrated to dryness. The residue was
purified by silica gel chromatography (hexane/ethyl acetate) to provide
the title compound (1.2 g) as colorless powder.
REFERENCE EXAMPLE 2-2
Ethyl 4-cyano-4,4-diphenylbutyrate
To an ethanolic solution (100 ml) of diphenylacetonitrile (28 g) were added
DBU (6 ml) and ethyl acrylate (30 ml) and the mixture was heated and
stirred at 80.degree. C. for 16 hours. After cooling, 200 ml of
2N-hydrochloric acid was added to the reaction mixture, which was then
extracted with isopropyl ether. The organic layer was washed with water,
dried (anhydrous magnesium sulfate) and concentrated under reduced
pressure. The resulting crude crystals were recrystallized from
hexane/isopropyl ether to provide ethyl 4-cyano-4,4-diphenylbutyrate (34
g).
In the same manner as above, the reference compounds 2-3.about.6 were
synthesized.
Compound 2-3
Ethyl 4-cyano-4-(p-fluorophenyl]-4-phenylbutyrate
Compound 2-4
Ethyl 4-cyano-4-(p-chlorophenyl)-4-phenylbutyrate
Compound 2-5
Ethyl 4-cyano-4,4-bis(p-chorophenyl)butyrate
Compound 2-6
Ethyl 5-cyano-5,5-diphenylpentanoate
The structural formulas, physical properties and NMR spectra of these
compounds are shown in Table 2.
TABLE 2
__________________________________________________________________________
##STR53##
Reference
Example
R.sup.0
Ar m .sup.1 HNMR (.delta..sub.ppm, CDCl.sub.3)
__________________________________________________________________________
2-1 H
##STR54##
2 1.11(3H, t), 3.42(2H, s), 4.07(2H, q), 7.26-7.43(10H,
m)
2-2 H
##STR55##
3
##STR56##
2-3 H
##STR57##
3
##STR58##
2-4 H
##STR59##
3
##STR60##
2-5 p-Cl
##STR61##
3
##STR62##
2-6 H
##STR63##
4
##STR64##
__________________________________________________________________________
REFERENCE EXAMPLE 3-1
2,2-Diphenyl-1,4-butanediol
In anhydrous THF (80 ml) was dissolved
.alpha.,.alpha.-diphenyl-.gamma.-butyrolactone (7 g) followed by addition
of lithium aluminum hydride (1 g) with ice-cooling, and the mixture was
stirred under the same conditions for 3 hours. Then, under ice-cooling, a
saturated aqueous solution of Rochelle salt was added dropwise to
precipitate the aluminum and other inorganic matter. The supernatant was
taken by decantation, dried and concentrated under reduced pressure. The
residue was recrystallized from isopropyl ether to provide
2,2-diphenyl-1,4-butanediol (7 g).
REFERENCE EXAMPLE 3-2
2-Diphenyl-1,5-pentanediol
In THF (120 ml) was dissolved ethyl 4-cyano-4,4diphenylbutyrate (24 g) and
the solution was added portionwise to a suspension of lithium aluminum
hydride (4.2 g) in THF (200 ml) with ice-cooling. The mixture was stirred
under ice-cooling for 2 hours, at the end of which time 2N-hydrochloric
acid (200 ml) was added and the mixture was heated and stirred at
60.degree. C. for 2 hours. Then, ethyl acetate (400 ml) was added to the
reaction mixture and the organic layer was separated, stirred and
concentrated under reduced pressure. The residue was dissolved in THF (200
ml) followed by addition of lithium aluminum hydride (4 g) with
ice-cooling. The mixture was stirred under the same conditions for 2
hours, after which a saturated aqueous solution of Rochelle salt was added
to the reaction mixture under ice-cooling to precipitate the aluminum and
other inorganic matter. The supernatant was taken by decantation, dried
and concentrated under reduced pressure. The residue was recrystallized
from isopropyl ether/ethyl acetate to provide 2-diphenyl-1,5-pentanediol
(20.5 g).
In the same manner as Reference Example 3-2, the following compounds
3-3.about.6 were synthesized.
Compound 3-3
2-(p-Fluorophenyl)-2-phenyl-1,5-pentanediol
Compound 3-4
2-(p-Chlorophenyl)-2-phenyl-1,5-pentanediol
Compound 3-5
2,2-Bis(p-chlorophenyl)-1,5-pentanediol
Compound 3-6
2,2-Diphenyl-1,6-hexanediol
The structural formulas, physical properties and NMR spectra of the above
compounds are shown in Table 3.
TABLE 3
__________________________________________________________________________
##STR65##
Reference
Example
R.sup.0
Ar m .sup.1 HNMR (.delta..sub.ppm, CDCl.sub.3)
__________________________________________________________________________
3-1 H
##STR66##
2 2.54(2H, t), 3.61(2H, t), 4.21(2H, s), 7.16-7.45(10H,
m)
3-2 H
##STR67##
3
##STR68##
3-3 H
##STR69##
3 1.32(2H, m), 2.22(2H, m), 3.59(2H, t), 4.13(2H, s),
6.90-7.40(9H, m)
3-4 H
##STR70##
3
##STR71##
3-5 p-Cl
##STR72##
3 1.20-1.40(2H, m), 2.20(2H, m), 3.60(2H, t), 4.10(2H,
s), 7.00-7.30(9H, m)
3-6 H
##STR73##
4
##STR74##
__________________________________________________________________________
REFERENCE EXAMPLE 4-1
4-(2-Hydroxyethyl)-4-phenylisochroman
In trifluoroacetic acid (50 ml) was dissolved 2,2-diphenyl-1,4-butanediol
(5 g) followed by addition of paraformaldehyde (1.7 g) and the mixture was
heated and stirred at 50.degree. C. for 2 hours. The reaction mixture was
then concentrated under reduced pressure and the residue was dissolved in
ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate
solution and concentrated under reduced pressure. The residue was
dissolved in ethanol (100 ml) followed by addition of sodium hydroxide (4
g) and water (50 ml) and the mixture was stirred at room temperature for 1
hour. After concentration under reduced pressure, the residue was
dissolved in ethyl acetate, washed with water, dried and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography using isopropyl ether/ethyl acetate as the eluent to
provide 4-(2-hydroxyethyl)-4-phenylisochroman (4.5 g).
In the same manner as Reference Example 4-1, the following Reference
Example Compounds 4-2.about.6 were synthesized.
Compound 4-2
4-(3-Hydroxypropyl)-4-phenylisochroman
Compound 4-3
4-(p-Fluorophenyl)-4-(3-hydroxypropyl)isochroman
Compound 4-4
4-(p-Chlorophenyl)-4-(3-hydroxypropyl)isochroman
Compound 4-5
7-Chloro-4-(p-chlorophenyl)-4-(3-hydroxypropyl)isochroman
Compound 4-6
4-(4-Hydroxybutyl)-4-phenylisochroman
The 'structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Table 4.
TABLE 4
__________________________________________________________________________
##STR75##
Reference Melting
Example
R.sup.0
Ar m Point (.degree.C.)
.sup.1 HNMR (.delta..sub.ppm,
__________________________________________________________________________
CDCl.sub.3)
4-1 H
##STR76##
2 Syrup
##STR77##
4-2 H
##STR78##
3 Syrup
4-3 H
##STR79##
3 Syrup
##STR80##
4-4 H
##STR81##
3 Syrup
##STR82##
4-5 7-Cl
##STR83##
3 Syrup
##STR84##
4-6 H
##STR85##
4 Syrup
##STR86##
__________________________________________________________________________
REFERENCE EXAMPLE 5-1
4-(2-Iodoethyl)-4-phenylisochroman
In dichloromethane (20 ml) was dissolved
4-(2-hydroxyethyl)-4-phenylisochroman (1 g), followed by addition of tosyl
chloride (0.85 g) and triethylamine (1.5 ml) with ice-cooling. The mixture
was stirred at room temperature for 2 hours, after which 2N-hydrochloric
acid was added and the mixture was extracted with isopropyl ether. The
organic layer was washed with water, dried and concentrated under reduced
pressure. The residue was dissolved in acetone (50 ml) and after addition
of sodium iodide (2 g) the solution was heated and stirred at 50.degree.
C. for 24 hours. After cooling, the reaction mixture was diluted with
water and extracted with isopropyl ether and the organic layer was washed
with water, dried and concentrated under reduced pressure. The residue was
applied to a silica gel column and eluted with isopropyl ether to provide
4-(2-iodoethyl)-4-phenylisochroman as oil.
In the same manner as Reference Example 5-1, the following Reference
Example Compounds 5-2.about.6 were synthesized.
Compound 5-2
4-(3-Iodopropyl)-4-phenylisochroman
Compound 5-3
4-(p-Fluorophenyl)-4-(3-iodopropyl)isochroman
Compound 5-4
4-(p-Chlorophenyl)-4-(3-iodopropyl)isochroman
Compound 5-5
7-Chloro-4-(p-chlorophenyl)-4-(3iodopropyl)isochroman
Compound 5-6
4-(4-Iodobutyl)-4-phenylisochroman
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Table 5.
TABLE 5
__________________________________________________________________________
##STR87##
Reference Melting
Example
R.sup.0
Ar L m Point (.degree.C.)
.sup.1 HNMR (.delta..sub.ppm,
__________________________________________________________________________
CDCl.sub.3)
5-1 H
##STR88##
I 2 Syrup
##STR89##
5-2 H
##STR90##
I 3 39-40
##STR91##
5-3 H
##STR92##
I 3 Syrup
##STR93##
5-4 H
##STR94##
I 3 Syrup
##STR95##
5-5 7-Cl
##STR96##
I 3 Syrup
##STR97##
5-6 H
##STR98##
I 4 Syrup
##STR99##
__________________________________________________________________________
REFERENCE EXAMPLE 6-1
1-Benzoyl-2-(2-phenylethyl)-2-piperidinecarbonitrile
##STR100##
To 200 ml of tetrahydrofuran containing 140 mmol lithium diisopropylamide
was added 15 g of solid 1-benzoyl-2-piperidinecarbonitrile at -78.degree.
C. The mixture was stirred for 30 minutes, after which 100 ml of
tetrahydrofuran containing 33.2 g of phenethyl iodide was added dropwise
at -78.degree. C. After completion of dropwise addition, the temperature
of the reaction mixture was gradually increased to 0.degree. C. Then,
water was added and the organic layer was separated. The aqueous layer was
further extracted with ethyl acetate. The pooled organic layer was dried
over anhydrous magnesium sulfate and filtered and the solvent was then
distilled off. The residue was purified by silica gel column
chromatography using ethyl acetate-hexane (1:2) as the eluent. The
solution containing the desired compound was distilled under reduced
pressure and the resulting solid was recrystallized from ethyl
acetate-hexane to provide 17.3 g of colorless crystals.
m.p. 65.degree.-67.degree. C.
.sup.1 N-NMR (ppm. CDCl.sub.3) 1.52-2.00 (4H, m), 2.19 (2H, t, J=6Hz),
2.37-2.98 (4H, m), 3.29-3.57 (2H, m), 7.13-7.56 (10H, m)
Elemental analysis for C.sub.21 H.sub.22 N.sub.2 O Calcd. C 79.21; H 6.96;
N 8.80; Found C 79.13; H 6.89; N 8.64
In the same manner as Reference Example 6-1, the following compounds were
synthesized.
REFERENCE EXAMPLE 6-2
1-Benzoyl-2-[2-(3-methoxyphenyl)ethyl]-2-piperidinecarbonitrile
REFERENCE EXAMPLE 6-3
1-Benzoyl-2-[2-(3,4-dimethoxyphenyl)ethyl]-2-piperidinecarbonitrile
REFERENCE EXAMPLE 6-4
1-Benzoyl-2-[2-thienylethyl]-2-piperidinecarbonitrile
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Table 6.
TABLE 6
__________________________________________________________________________
Re- Melting Elemental Analysis
ference
Structural Point [Found/(Calculated)]
Example
Formula (.degree.C.)
NMR (.delta..sub.ppm, CDCl.sub.3)
C H N
__________________________________________________________________________
6-2
##STR101## 82-84
##STR102##
##STR103##
6-3
##STR104## Oil
##STR105##
##STR106##
6-4
##STR107## Oil
##STR108##
##STR109##
__________________________________________________________________________
REFERENCE EXAMPLE 6-5
3,4-Dihydrospiro[naphthalene-2(1H), 2'-piperidin]-1-one hydrochloride
##STR110##
In 250 ml of 1,2-dichloroethane was dissolved 7.64 g of
1-benzoyl-2-(2-phenylethyl)-2piperidinecarbonitrile. Then, 8.0 g of
aluminum chloride was added and the mixture was refluxed for 6 hours. The
reaction mixture was cooled and poured cautiously into 10% aqueous sodium
hydroxide solution. Then, methylene chloride and water were added for
extraction. The methylene chloride layer was dried over anhydrous sodium
sulfate and filtered and the solvent was distilled off. To the residue
were added 100 ml of methanol and 100 ml of 20% aqueous sodium hydroxide
solution and the mixture was refluxed for 12 hours. After the reaction
mixture was allowed to cool, the methanol was distilled off and methylene
chloride and water were added for extraction. The methylene chloride layer
was dried over anhydrous sodium sulfate and filtered and the solvent was
then distilled off. The residue was purified by alumina column
chromatography using an ethyl acetate-hexane solvent system and the eluate
containing the desired compound was distilled under reduced pressure. The
residue was treated with 6.0 ml of 4N-methanolic HCl to provide a solid.
This solid was recrytallized from methylene chloride to provide 3.0 g of
colorless crystals.
m.p. 222.degree.-223.degree. C.
.sup.1 H-NMR (ppm, CDCl.sub.3) 1.37-1.85 (5H, m), 1.92-2.14 (3H, m), 2.44
(1H, dt, J=7Hz, 5Hz), 2.76-3.16 (4H, m), 7.20-7.52 (3H, m), 8.29 (1H, dd,
J=8Hz, 1Hz)
Elemental analysis for C.sub.14 H.sub.18 ClNO.H.sub.2 O Calcd. C 62.33; H
7.47; N 5.19; Found C 62.39; H 7.27; N 5.42
In the same manner as Reference Example 6-5, the following compounds were
synthesized.
REFERENCE EXAMPLE 6-6
3,4-Dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidin]-1-one
hydrochloride
REFERENCE EXAMPLE 6-7
3,4-Dihydro-8-methoxyspiro[naphthalene-2(1H),2'-piperidin]-1-one
hydrochloride
REFERENCE EXAMPLE 6-8
3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidin]-1-one
hydrochloride
REFERENCE EXAMPLE 6-9
6,7-Dihydrospiro[benzo(b)thiophene-5 (4H),2'-piperidin]-4-one hydrochloride
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Table 7.
TABLE 7
__________________________________________________________________________
Elemental Analysis
Reference
Structural Melting [Found/(Calculated)]
Example
Formula Point (.degree.C.)
NMR (.delta..sub.ppm,
C H N3)
__________________________________________________________________________
6-6
##STR111##
##STR112##
##STR113##
##STR114##
6-7
##STR115##
##STR116##
##STR117##
##STR118##
6-8
##STR119##
##STR120##
##STR121##
##STR122##
6-9
##STR123## >280
##STR124##
##STR125##
__________________________________________________________________________
REFERENCE EXAMPLE 6-10
3,4-Dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-ol
##STR126##
In 20 ml of methanol was dissolved 0.80 g of
3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-one. Then, 0.15 g of
sodium borohydride was added portionwise. The mixture was stirred for 30
minutes, after which it was diluted with water and extracted with
methylene chloride. The methylene chloride layer was dried over anhydrous
sodium sulfate and filtered and the solvent was then distilled off. The
solid residue was recrystallized from methylene chloride-ether to provide
0.25 g of white crystals.
m.p. 125.degree.-127.degree. C.
.sup.1 H-NMR (ppm, CDCl.sub.3) 1.32-1.98 (8H, m), 2.28 (1H, q, J=7Hz),
2.74-2.94 (4H, m), 4.37 (1H, s), 7.07-7.28 (4H, m), 7.40-7.52 (1H, m)
Elemental analysis for C.sub.14 H.sub.19 NO
Calcd. C 77.38; H 8.81; N 6.45; Found C 77.16; H 8.84; N 7.01
In the same manner as Reference Example 6-10, the following compounds were
synthesized.
REFERENCE EXAMPLE 6-11
3,4-Dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidin)-1-ol
REFERENCE EXAMPLE 6-12
3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidin)-1-ol
hydrochloride
REFERENCE EXAMPLE 6-13
6,7-Dihydrospiro[benzo[b]thiophene-5(4H),2'-piperidin)-4-ol hydrochloride
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Table 8.
TABLE 8
__________________________________________________________________________
Elemental Analysis
Reference
Structural Melting [Found/(Calculated)]
Example
Formula Point (.degree.C.)
NMR (.delta..sub.ppm,
C H N3)
__________________________________________________________________________
6-11
##STR127## 132-134
##STR128##
##STR129##
6-12
##STR130##
##STR131##
##STR132##
##STR133##
6-13
##STR134##
##STR135##
##STR136##
##STR137##
__________________________________________________________________________
REFERENCE EXAMPLE 6-14
3,4-Dihydrospiro[naphthalene-2(1H),2'-piperidine] hydrochloride
##STR138##
(1) To 200 ml of a methylene chloride solution containing 3.36 g of
3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-one was added 2.6 g of
potassium carbonate. Then, 50 ml of a methylene chloride solution
containing 3.4 ml of trifluoroacetic anhydride was added dropwise at
0.degree. C. and the mixture was stirred for 3 hours. The reaction mixture
was diluted with water and extracted with methylene chloride. The
methylene chloride layer was dried over anhydrous magnesium sulfate and
filtered and the solvent was then distilled off. The residue was purified
by silica gel column chromatography using ethyl acetate/hexane (1:2) as
the eluent and the eluate containing the desired compound was distilled
under reduced pressure. The solid residue was recrystallized from ethyl
acetate-hexane to provide 4.86 g of
1'-trifluoroacetyl-3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-one
as colorless needles.
m.p. 97-100.degree. C.
.sup.1 H-NMR (ppm, CDCl.sub.3) 1.60-2.25 (7H, m), 2.67-3.16 (3H, m),
3.35-3.53 (1H, m), 3.82-3.98 (1H, m), 7.16-7.52 (3H, m), 8.20 (1H, dd, J=8
Hz, 1.2 Hz)
Elemental analysis for C.sub.16 H.sub.16 F.sub.3 NO.sub.2 Calcd. C 61.73; H
5.18; N 4.50; Found C 61.47; H 5.20; N 4.40.
(2) In 30 ml of acetic acid was dissolved 4.44 g of
1'-trifluoroacetyl-3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-one
and using 0.76 g of 10% palladium-on-carbon as the catalyst, catalytic
reduction was carried out at 4 kg/cm.sup.2 and 80.degree. C. The reaction
mixture was then poured in water, made basic with 10% aqueous sodium
hydroxide solution and extracted with methylene chloride. The methylene
chloride layer was dried over anhydrous sodium sulfate and filtered and
the solvent was then distilled off. The residue was treated with 3.6 ml of
4N-methanolic HCl to give a solid. This solid was recrystallized from
methylene chloride-ether to provide 2.51 g of white crystals.
m.p. 200.degree.-202.degree. C. .sup.1 H-NMR (ppm, CDCl.sub.3) 1.43-1.80
(8H, m), 1.84-2.02 (1H, m), 2.77 (2H, s), 2.84 (4H, t, J=5Hz), 7.10 (4H,
s)
Elemental analysis for C.sub.14 H.sub.20 ClN.1/4H.sub.2 O Calcd. C 69.40; H
8.53; N 5.78; Found C 69.62; H 8.38; N 5.64
REFERENCE EXAMPLE 6-15
3,4-Dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride
##STR139##
In 30 ml of trifluoroacetic acid was dissolved 6.57 g of
3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidin]-1-one followed
by addition of 8.5 ml of triethylsilane and the mixture was stirred for 1
hour. This reaction mixture was poured portionwise in water and after
addition of 1N-hydrochloric acid, washed with hexane. The aqueous layer
was made basic with 1N-aqueous sodium hydroxide solution and extracted
with methylene chloride. The methylene chloride layer was dried over
anhydrous sodium sulfate and filtered and the solvent was then distilled
off. The residue was treated with 7.0 ml of 4N-methanolic HCl to give a
solid. This solid was recrystallized from methanolether to provide 5.09 g
of white crystals.
m.p. 201.degree.-203.degree. C.
.sup.1 H-NMR (ppm, CDCl.sub.3) 1.31-2.00 (9H, m), 2.71 (2H, s), 2.74-2.88
(4H, m), 3.77 (3H, m), 6.62-6.73 (2H, m), 6.98 (1H, m)
Elemental analysis for C.sub.15 H.sub.22 ClNO.1/5H.sub.2 O Calcd. C 66.38;
H 8.32; N 5.16; Found C 66.65; H 8.46; N 5.03
In the same manner as Reference Example 6-15, the following compounds were
synthesized.
REFERENCE EXAMPLE 6-16
3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]
hydrochloride
REFERENCE EXAMPLE 6-17
3,4-Dihydro-8-methoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride
REFERENCE EXAMPLE 6-18
6,7-Dihydrospiro[benzo[b]thiophene-5(4H),2'-piperidine]hydrochloride
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Table 9.
TABLE 9
__________________________________________________________________________
Re- Melting Elemental Analysis
ference
Structural Point [Found/(Calculated)]
Example
Formula (.degree.C.)
NMR (.delta..sub.ppm, CDCl.sub.3)
C H N
__________________________________________________________________________
6-16
##STR140## 205-208
##STR141##
##STR142##
6-17
##STR143## 239-241
##STR144##
##STR145##
6-18
##STR146## 212-220
##STR147##
##STR148##
__________________________________________________________________________
REFERENCE EXAMPLE 7-1
4-Amino-3,3-diphenylbutanol
To a solution of ethyl 3-cyano-3,3-diphenylpropionate (reference compound
2-1) (1.2 g) in tetrahydrofuran (30 ml) was added lithium aluminum hydride
(0.44 g) portionwise with ice-cooling and stirring. After completion of
dropwise addition, the mixture was heated and stirred at 60.degree. C. for
3 hours. The reaction mixture was then cooled with ice again, and water (1
ml), 15% aqueous sodium hydroxide solution (3 ml) and water (1 ml) were
added in the order mentioned. The resulting precipitate was filtered off
and the filtrate was extracted using ethyl acetate and saturated aqueous
sodium hydrogen carbonate solution. The organic layer was separated,
washed with water, dried over anhydrous sodium sulfate, and concentrated
to dryness. The residue was washed with ethyl acetate to provide the title
compound (0.82 g) as colorless powder.
Reference Example Compounds 7-2.about.4 were synthesized from reference
compound 2-2, 2-4 and 2-5 respectively in the same manner as Reference
Example 7-1.
Compound 7-2
5-Amino-4,4-diphenylpentanol
Compound 7-3
5-Amino-4-(p-chlorophenyl)-4-phenylpentanol
Compound 7-4
5-Amino-4,4-bis(p-chlorophenyl)pentanol
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Table 10.
TABLE 10
__________________________________________________________________________
##STR149##
Reference Melting
Example
R.sup.0
Ar m Point (.degree.C.)
.sup.1 HNMR (.delta..sub.ppm,
__________________________________________________________________________
CDCl.sub.3)
7-1 H
##STR150##
2 131-133
2.32(2H, t), 3.15(2H, t), 3.23(2H, s),
7.10-7.33(10H, m)
7-2 H
##STR151##
3 Syrup
7-3 H
##STR152##
3 Syrup
##STR153##
7-4 p-Cl
##STR154##
3 Syrup
##STR155##
__________________________________________________________________________
REFERENCE EXAMPLE 8-1
4-Formylamino-3,3-diphenylbutanol
In formic acid (100 ml) was dissolved 4-amino-3,3-diphenylbutanol
(reference compound 7-1) (17.1 g) followed by addition of acetic anhydride
(16 ml) and the mixture was stirred at room temperature for 7 hours. The
reaction mixture was concentrated to dryness and the residue was
distributed between chloroform and water. The aqueous layer was made basic
with aqueous ammonia and extracted with chloroform. The extract was dried
over anhydrous sodium sulfate and concentrated to dryness. The residue was
dissolved in ethanol (50 ml) and the solution was stirred with 1N-sodium
hydroxide solution (60 ml) at room temperature for 15 minutes. To this
reaction mixture was added water and the resulting crystals were recovered
by filtration. The crystals were washed serially with water and ethyl
acetate to provide the title compound (16 g) as colorless powder.
The following Reference Example Compounds 8-2.about.4 were synthesized in
the same manner as Reference Example 8-1.
Compound 8-2
5-Formylamino-4,4-diphenylpentanol
Compound 8-3
4-(p-Chlorophenyl)-5-formylamino-4-phenylpentanol
Compound 8-4
4,4-Bis(p-chlorophenyl)-5-formylaminopentanol
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Table 11.
TABLE 11
__________________________________________________________________________
##STR156##
Reference Melting
Example
R.degree.
Ar m Point (.degree.C.)
.sup.1 HNMR (.delta..sub.ppm,
__________________________________________________________________________
CDCl.sub.3)
8-1 H
##STR157##
2 133-135
2.28(2H, t), 3.17(2H, q), 3.90(2H, d), 4.37(1H,
t), 7.11-7.34 (10H, m), 7.48(1H, br t),
7.88(1H, d)
8-2 H
##STR158##
3 151-152
1.32(2H, m), 2.16(2H, m), 3.55(2H, t), 4.05(2H,
d), 5.10-5.30 7.10-7.40(10H, m), 8.08(1H, d).
8-3 H
##STR159##
3 159-161
1.00-1.23(2H, m), 2.03(2H, t), 3.30(2H, q),
3.88(2H, dd), 4.33 (1H, t), 7.10-7.37(9H, m),
7.48(1H, br t), 7.87(1H, d)
8-4 p-Cl
##STR160##
3 175-178
1.00-1.20(2H, m), 2.04(2H, t), 3.30(2H, q),
3.86(2H, d), 4.34 (1H, t), 7.10-7.40(8H, m),
7.55(1H, br t), 7.88(1H, d)
__________________________________________________________________________
REFERENCE EXAMPLE 9-1
4-Formylamino-3,3-diphenylbutyl tosylate
To a suspension of 4-formylamino-3,3-diphenylbutanol (21.5 g) in methylene
chloride (250 ml) were added triethylamine (22 ml),
4-dimethylaminopyridine (catalyst amount) and tosyl chloride (15.3 g) and
the mixture was stirred at room temperature for 16 hours. The reaction
mixture was concentrated to dryness and dissolved in water-ethyl acetate.
The ethyl acetate layer was washed with 1N-hydrochloric acid, further
washed with water, dried over anhydrous sodium sulfate, and concentrated
to dryness. The residue was purified by silica gel column chromatography
(n-hexane: ethyl acetate 4:1.about.1:1) to provide the title compound (32
g) as colorless syrup.
Reference Example compound 9-4 was synthesized in the same manner as
Reference Example 9-1.
Compound 9-4
4,4-Bis(p-chlorophenyl)-5-(formylamino)pentyl tosylate
REFERENCE EXAMPLE 9-2
5-Formylamino-1-iodo-4,4-diphenylpentane
To a solution of 5-formylamino-4,4-diphenylpentanol (38.3 g) in methylene
chloride (600 ml) were added p-toluenesulfonyl chloride (29.2 g),
triethylamine (15 g) and a catalyst amount of 4,4-dimethylaminopyridine
and the mixture was stirred at room temperature for 4 hours. The reaction
mixture was then concentrated to dryness and sodium iodide (46.6 g) and
acetone (600 ml) were added to the residue. The mixture was heated and
stirred at 50.degree. C. for 2 hours, after which it was concentrated to
dryness. The residue was extracted with ethyl acetate and water. The
organic layer was separated and washed with aqueous sodium thiosulfate
solution. It was dried over anhydrous sodium sulfate and concentrated to
dryness and the residue was purified by silica gel column chromatography
to provide the title compound (46.5 g) as yellow syrup.
Reference Example Compound 9-3 was synthesized in the same manner as
Reference Example 9-2.
Compound 9-3
4-(p-Chlorophenyl)-5-formylamino-1-iodo-4-phenylpentane
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Table 12.
TABLE 12
__________________________________________________________________________
##STR161##
Reference Melting
Example
R.degree.
Ar L m Point (.degree.C.)
.sup.1 HNMR (.delta..sub.ppm,
__________________________________________________________________________
CDCl.sub.3)
9-1 H
##STR162##
OTs
2 Syrup 2.45(3H, s), 2.52(2H, t), 3.87(2H, t),
3.96(2H, d), 5.00-5.20 (1H, br),
7.00-7.40(12H, m), 7.67(2H, d), 8.08(1H,
d).
9-2 H
##STR163##
I 3 Syrup 1.49-1.65(2H, m), 2.12-2.25(2H, m), 3.10(2H,
t), 4.04(2H, d), 5.07(1H, br t),
7.11-7.40(10H, m), 8.11(1H, d)
9-3 H
##STR164##
I 3 Syrup 1.46-1.63(2H, m), 2.10-2.22(2H, m), 3.10(2H,
t), 4.01(2H, d), 5.08(1H, br t),
7.06-7.39(9H, m), 8.10(1H, d)
9-4 p-Cl
##STR165##
OTs
3 Syrup 2.45(3H, s), 3.90-4.00(4H, m), 5.00-5.20(1H,
Br, 7.00-7.40 (10H, m), 7.72(2H, m),
8.08(1H, d).
__________________________________________________________________________
REFERENCE EXAMPLE 10-1
1-[4-(p-Fluorophenyl)piperazin-1-yl]-4-formylamino-3,3-diphenylbutane
dihydrochloride
A mixture of 4-formylamino-3,3-diphenylbutyl tosylate (7 g) and
1-(p-fluorophenyl)piperazine (5.2 g) was heated in acetonitrile (50 ml) at
60.degree. C. with stirring for 4 hours. The reaction mixture was then
concentrated to dryness and dissolved in water-ethyl acetate. The ethyl
acetate layer was washed with water, dried over anhydrous sodium sulfate
and concentrated to dryness. The residue was purified by silica gel column
chromatography (ethyl acetate) and treated with hydrochloric acid to
provide the title compound (7 g) as white crystals.
Reference Example Compounds 10-2, 10-4.about.8 and 10-10.about.12 were
respectively synthesized in the same manner as Reference Example 10-1.
Compound 10-2
5-Formylamino-1-morpholino-4,4-diphenylpentane hydrochloride
Compound 10-4
5-Formylamino-1-[2,3,4,5-tetrahydro-1(H)-3-benzazepin-3-yl]-4,4-diphenylpen
tane hydrochloride
Compound 10-5
5-Formylamino-1-dimethylamino-4,4-diphenylpentane
Compound 10-6
1-(N-Benzyl-N-methylamino)-5-formylamino-4,4-diphenylpentane hydrochloride
Compound 10-7
5-Formylamino-4,4-diphenyl-1-(4-phenylpiperazin-1yl)pentane
Compound 10-8
1-[4-(p-Fluorophenyl)piperazin-1-yl]-5-formylamino-4,4-diphenylpentane
dihydrochloride
Compound 10-10
4-(p-Chlorophenyl)-5-formylamino-4-phenyl-1-(4-phenylpiperazin-1-yl)pentane
dihydrochloride
Compound 10-11
4-(p-Chlorophenyl)-5-formylamino-4-phenyl-1-(4phenylpiperidino)pentane
hydrochloride
Compound 10-12
4,4-Bis(p-chlorophenyl)-1-[4-(p-fluorophenyl)-piperazin-1-yl]-5-(formylamin
o)pentane dihydrochloride
REFERENCE EXAMPLE 10-3
N-(5-Formylamino-4,4-diphenylpentyl)phthalimide
A mixture of 5-formylamino-1-iodo-4,4-diphenylpentane (7 g) and potassium
phthalimide (3.63 g) was stirred in DMF (40 ml) at room temperature for 3
hours. The reaction mixture was poured in ice-water and the syrup which
separated out was extracted with ethyl acetate. The extract was washed
with water, dried over anhydrous sodium sulfate and concentrated to
dryness. The residue was washed with isopropyl ether to provide the title
compound (5.2 g) as colorless powder.
Reference Example Compound 10-9 was synthesized in the same manner as
Reference Example 10-3.
Compound 10-9
N-[4-(p-Chlorophenyl)-5-formylamino-4-phenylpentyl]phthalimide
The structural formulas, physical properties and NMR spectra of the above
compounds are shown in Tables 13 and 14.
TABLE 13
-
##STR166##
R
eference Example R' R.degree. Ar m x Melting Point (.degree.C.) NMR
(.delta..sub.ppm, CDCl.sub.3)
10-1
##STR167##
H
##STR168##
2 2 145-148 2.10-2.40(4H, m), 2.52(4H, t), 3.08(4H, t), 4.05(2H,
d),5.60-5.80(1H, br s), 6.80-7.00(4H, m), 7.10-7.40(10H, m),8.12(1H, d).
10-2
##STR169##
H
##STR170##
3 1 Noncrystal-line powder 1.26(2H, m), 2.00-2.30(6H, m), 3.64(4H, t),
4.04(2H,d), 5.00-5.20(1H, br), 7.10-7.40(9H, m), 8.09(1H, d).
10-3
##STR171##
H
##STR172##
3 -- 171-172 1.40-1.58(2H, m), 2.05-2.20(2H, m), 3.61(2H, t), 4.00(2H,
d), 5.00(1H, br t), 7.05-7.32(10H, m), 7.64-7.76(2H, m), 7.75-7.85(2H,
m), 8.02(1H, d)
10-4
##STR173##
H
##STR174##
3 1 123-126 1.29(2H, m), 2.09(2H, m), 2.38(4H, t), 2.49(4H, m)2.84(4H,
m), 4.05 (2H, d), 5.10(1H, br s), 7.00-7.40(14H, m), 8.09(1H, d).
10-5 N(CH.sub.3).sub.2 H
##STR175##
3 -- 98-99 1.12-1.31(2H, m), 2.04-2.22(4H, m), 2.09(6H, s), 4.05(2H,
d), 5.16(1H, br s), 7.13-7.37(10H, m), 8.09(1H, d)
10-6
##STR176##
H
##STR177##
3 1 97-105 1.20-1.36(2H, m), 2.04(3H, s), 2.02-2.15(2H, m), 2.28(2H,
t), 3.36(2H, s), 4.04(2H, d), 5.11(1H, br t),7.10-7.37(15H, m), 8.06(1H,
d)
10-7
##STR178##
H
##STR179##
3 -- Syrup 1.20-1.39(2H, m), 2.04-2.20(2H, m), 2.30(2H, t), 2.45(4H,
t), 3.13(4H, t), 4.06(2H, d), 5.09(1H, br t),6.79-6.92(3H, m), 7.12-7.37(
12H, m), 8.09(1H, d)
10-8
##STR180##
H
##STR181##
3 2 Noncrystal-line powder 1.20-1.40(2H, m), 2.10-2.40(4H, m), 2.45(4H,
t), 3.05(4H, t), 4.06(2H, d), 5.10(1H, br s), 6.80-7.00(4H, m),7.10-7.40(
10H, m), 8.10(1H, d).
TABLE 14
- Reference Example R' R.degree. Ar m x Melting Point (.degree.C.) NMR
(.delta..sub.ppm, CDCl.sub.3)
10-9
##STR182##
H
##STR183##
3 -- Noncrystal-line powder 1.37-1.60(2H, m), 2.03-2.19(2H, m),
3.61(2H, t), 3.97(2H, q), 5.00(1H, br s), 6.99-7.33(9H, m), 7.65-7.83(4H,
m), 8.02(1H, s)
10-10
##STR184##
H
##STR185##
3 2 133-138 1.20-1.36(2H, m), 2.03-2.15(2H, m), 2.31(2H, t), 2.46(4H,
t), 3.14(4H, t), 4.03(2H, d), 5.10(1H, br t),6.80-6.93(3H, m), 7.06-7.38(
11H, m), 8.10(1H, d)
10-11
##STR186##
H
##STR187##
3 1 118-123 1.20-1.39(2H, m), 1.40-2.19(8H, m), 2.29(2H, t),2.32-2.53(1H
, m), 2.89(2H, d), 4.03(2H, dd), 5.21(1H, br t), 7.06-7.37(14H, m),
8.19(1H, d)
10-12
##STR188##
p-Cl
##STR189##
3 2 Noncrystal-line powder 1.20-1.40(2H, m), 2.10-2.40(4H, m), 2.46(4H,
t), 3.06(4H, t), 4.00(2H, d), 5.10(1H, br s), 6.80-7.30(12H, m)8.10(1H,
d).
REFERENCE EXAMPLE 11-1
4-Bromo-3,4-dihydro-5-oxo-1-[2,4,6-(triisopropyl)benzenesulfonyl]-5H-benz[c
d]indole
To a solution of
3,4-dihydro-5-oxo-1-[2,4,6-(triisopropyl)benzenesulfonyl]-5H-benz[cd]indol
e (11 g; 75% purity) in THF (80 ml) was slowly added
phenyltrimethylammonium tribromide [7.15 g in THF (25 ml)] at -45.degree.
C. The mixture was stirred from -45.degree. C. to room temperature for one
hour and filtrated off. The solution was concentrated and the residue was
washed with ether to give the titled compound as pale a yellow powder (8.9
g).
Reference Example Compound 11-2 was synthesized as a same manner with
Reference Example 11-1.
Compound 11-2
4-Bromo-3,4-dihydro-6-methoxy-5-oxo-1-(p-toluenesulfonyl)-5H-benz[cd]indole
REFERENCE EXAMPLE 11-3
4-Azido-3,4-dihydro-5-oxo-1-[2,4,6-(triisopropyl)benzenesulfonyl]-5H-benz[c
d]indole
To a solution of
4-bromo-3,4-dihydro-5-oxo-1-[2,4,6-(triisopropyl)benzenesulfonyl]-5H-benz[
cd]indole [11.9 g in DMF (200 ml)] was added acetic acid (3.3 ml) followed
by aqueous sodium azide [3.3 g in water (22 ml)] at -25.degree. C. The
mixture was warmed to -10.degree. C. and stirred at -10.degree. C. for 30
min and poured into the ice-water. The precipitate was filtrated, washed
with water, and dried to give the titled compound as a yellow powder (10.3
g).
Reference Example compound 11-4 was synthesized as same manner with
Reference Example 11-3.
Compound 11-4
4-Azido-3,4-dihydro-6-methoxy-5-oxo-1-(p-toluenesulfonyl)-5H-benz[cd]indole
REFERENCE EXAMPLE 11-5
4-Acetylamino-3,4-dihydro-5-oxo-1-[2,4,6-(triisopropyl)benzenesulfonyl]-5H-
benz[cd]indole
The mixture of
4-Azido-3,4-dihydro-5-oxo-1-[2,4,6-(triisopropyl)benzenesulfonyl]-5H-benz[
cd]indole (10.3 g) and acetic anhydride (4.4 g) in THF (150 ml) was
hydrogenated over 10% Pd-carbon (3 g) at room temperature for four hours.
The catalyst was filtered and the filtrate was concentrated. The residue
was recrystalized from hexane/isopropyl ether to give the titled compound
as a pale yellow powder (9.3 g).
Reference Example Compound 11-6 was synthesized as same manner with
Reference example 11-5.
Compound 11-6
4-Acetylamino-3,4-dihydro-6-methoxy-5-oxo-1-(p-toluenesulfonyl)-5H-benz[cd]
indole
REFERENCE EXAMPLE 11-7
1-[2,4,6-(Triisopropyl)benzenesulfonyl]spiro{benz[cd]indole-4(3H,5H),2'-(1'
-acetylpiperidine}-5-one
Sodium hydride (0.6g, 60% purity) was washed with hexane and suspended in
DMF (20 ml). 1,4-Dibromobutane was added followed by
4-acetylamino-3,4-dihydro-5-oxo-1-[2,4,6-(triisopropyl)benzenesulfonyl]-5H
-benz[cd]indole [3.1 g in DMSO (10 ml)] at -13.degree. C. under the
nitrogen stream. The mixture was stirred at -13.degree. C. for 5 minutes
and at 0.degree. C. for 20 min. and then poured into the mixture of ice
and 1N hydrogen chloride. The separated oil was extracted with ethyl
acetate and the organic layer was washed with water, concentrated. The
residue was purified by silica gel chromatography and recrystalized from
hexane/isopropyl ether to give the titled compound as a yellow powder (2.3
g).
Reference Example Compound 11-8 was synthesized as same manner with
Reference Example 11-7.
Compound 11-8
6-Methoxy-1-[p-toluenesulfonyl]spiro{benz[cd]indole-4(3H,5H),
2'-(1'-acetylpiperidine)}-5-one
REFERENCE EXAMPLE 11-9
1-[2,4,6(Triisopropyl)benzenesulfonyl]spiro{benz[cd]indole-4(3H,5H),
2'-piperidine}-5-one
The mixture of
1-[2,4,6-(triisopropyl)benzenesulfonyl]spiro{benz[cd]indole-4(3H,5H),
2'-(1'-acetylpiperidine}-5-one (1.9 g), conc. hydrogen chloride (8 ml),
and ethanol (30 ml) was refluxed for 39 hours. The mixture was
concentrated and treated with ethyl acetate and saturated aqueous sodium
hydrogen sulfate. The organic phase was separated, washed with water, and
concentrated. The residue was purified by silica gel chromatography and
recrystalized from hexane to give the titled compound as a pale yellow
powder (1.4 g).
Reference Example compound 11-10 was synthesized as same manner with
Reference Example 11-9.
Compound 11-10
6-Methoxy-1-[p-toluenesulfonyl]spiro{benz[cd]indole-4(3H,5H),
2'-piperidine}-5-one
REFERENCE EXAMPLE 11-11
Spiro{1H-benz[cd]indole-4(3H,5H), 2'-piperidine}-5-one
1-[2,4,6-(Triisopropyl)benzenesulfonyl]spiro{benz[cd]indole-4(3H,5H),
2'-piperidine}-5-one (3.3 g) was refluxed with 1N-aqueous sodium hydroxide
(25 ml) and methanol (120 ml) for 24 hours. The mixture was concentrated
and the residue was washed with water to give the titled compound as a
yellow powder (1.5 g).
Reference Example compound 11-12 was synthesized as same manner with
Reference Example 11-9.
Compound 11-12
6-Methoxyspiro{1H-benz[cd]indole-4(3H,5H),2'-piperidine}-5-one
REFERENCE EXAMPLE 11-13
5-Hydroxyl-6-methoxy-1-(p-toluenesulfonyl)spiro{benz[cd]indole-4(3H,5H),2'-
piperidine}
To a solution of
6-methoxy-1-[p-toluenesulfonyl]spiro{benz[cd]indole-4(3H,5H),2'-piperidine
}-5-one (0.73 g) in THF (15 ml) was added lithium aluminum hydride (0.14 g)
as a portion wise manner at 0.degree. C. The mixture was refluxed for 24
hours. The mixture was cooled and treated with water. The precipitate was
filtered off and the filtrate was extracted with ethyl acetate. The
extract was washed with water and concentrated. The residue was purified
by silica gel chromatography and recrystalized from isopropyl ether/ethyl
acetate to give the titled compound (0.59 g) as a pale yellow powder.
REFERENCE EXAMPLE 11-14
6-Methoxy-1-(p-toluenesulfonyl)spiro{benz[cd]indole-4(3H,5H),2'-piperidine}
To a solution of
5-hydroxyl-6-methoxy-1-(p-toluenesulfonyl)spiro{benz[cd]indole-4(3H,5H),2'
-piperidine}in trifluoroacetic acid (20 ml) was added triethylsilane (6.5
ml) and the mixture was stirred at room temperature for 20 hours. The
mixture was concentrated and the residue was treated with ethyl acetate
and water. The aqueous phase was basified with aqueous ammonia and
extracted with ethyl acetate. The combined extract was washed with water
and concentrated. The residue was purified by silica gel chromatography to
give the titled compound (0.55 g) as a pale brown powder.
REFERENCE EXAMPLE 11-15
6-Methoxyspiro{1H-benz[cd]indole-4(3H,5H),2'-piperidine}
The mixture of
6-methoxy-1-(p-toluenesulfonyl)spiro{benz[cd]indole-4(3H,5H),2'-piperidine
}(0.55 g), methanol (15 ml), and 1N-aqueous sodium hydroxide (3 ml) was
refluxed for 90 min. The mixture was concentrated and the residue was
treated with ethyl acetate and water. The organic phase was washed with
water and concentrated. The residue was purified by silica gel
chromatography and recrystalized from acetone/isopropyl ether to give the
titled compound (0.19 g) as a white powder.
The structural formulas, yield and NMR spectra of the above compounds are
shown in Tables 15, 16 and 17.
TABLE 15
__________________________________________________________________________
Ref-
erence
Exam-
Structual
ple Formula Yield.sup.(%)
NMR (.delta..sub.ppm,
__________________________________________________________________________
CDCl.sub.3)
11-1
##STR190## 92 1.09, 1.12, 1.25(each 6H, d),
2.82-3.03(1H, m), 3.57(1H, dd),
3.84(1H, ddd), 4.07-4.28(2H, m), 4.83,
(1H, dd), 7.20(2H, s), 7.39(1H, s),
7.39(1H, t), 7.71, 7.79(each, 1H, d)
11-2
##STR191## 100 2.36, 3.97(each, 3H, s), 3.46(1H, dd),
4.72(1H, dd), 7.01, 8.09(each, 1H, d),
7.25, 7.75(each 2H, d), 7.45(1H, d)
11-3
##STR192## 94 1.10(12H, d), 1.25(6H, d),
2.82-3.03(1H, m), 3.15(1H, ddd),
3.48(1H, dd), 4.07-4.26(2H, m),
4.47(1H, dd), 7.20(2H, s), 7.30(1H,
s), 7.39(1H, t), 7.73, 7.76(each 1H,
d)
11-4
##STR193## 100 2.37, 3.98(each 3H, s), 3.01(1H, ddd),
3.33(1H, dd), 4.35 (1H, dd), 7.00,
8.08(each 1H, d), 7.25, 7.74(each 2H,
d), 7.37 (1H, s)
11-5
##STR194## 88 1.08, 1.13, 1.26(each 6H, d), 2.12(3H,
s), 2.82-3.03(1H, m), 2.82(1H, dd),
3.96(1H, dd), 4.07-4.28(2H, m),
4.79-4.92 (1H, m), 6.72(1H, br d),
7.21(2H, s), 7.23(1H, d), 7.38 (1H,
t), 7.70, 7.78(each 1H, d)
11-6
##STR195## 79 2.09, 2.37, 3.96(each 3H, s), 2.74(1H,
ddd), 3.85(1H, dd), 4.72(1H, ddd),
6.78(1H, br d), 6.97, 8.07(each 1H,
d), 7.25, 7.74(each 2H, d), 7.33(1H,
__________________________________________________________________________
d)
TABLE 16
__________________________________________________________________________
Ref-
erence
Exam-
Structual
ple Formula Yield.sup.(%)
NMR (.delta..sub.ppm,
__________________________________________________________________________
CDCl.sub.3)
11-7
##STR196## 67 1.08, 1.11, 1.25(each 6H, d),
1.52-1.90(6H, m), 2.14(3H, s),
2.81-3.02(1H, m), 3.20-3.58(3H, m),
3.75-3.89(1H, m), 4.08- 4.29(2H, m),
7.18(2H, s), 7.23(1H, d), 7.33(1H, t),
7.60, 7.81(each 1H, d)
11-8
##STR197## 74 1.54-1.84(6H, m), 2.09, 2.37,
3.94(each 3H, s), 3.13(1H, d),
3.31-3.58(2H, m), 3.65-3.80(1H, m),
6.96, 8.01(each 1H, d), 7.23.
7.71(each 2H, d), 7.26(1H, s)
11-9
##STR198## 100 1.08, 1.11, 1.25(each 6H, d),
1.40-1.90(6H, m), 2.80-3.11 (4H, m),
3.53 (1H, d), 4.09-4.29(2H, m),
7.19(2H, s), 7.28 (1H, d), 7.36(1H,
t), 7.66, 7.70(each 1H, d)
11-10
##STR199## 93 1.35-1.83(6H, m), 2.36, 3.96(each 3H,
s), 2.73-2.90(1H, m), 2.91, 3.35(each
1H, d), 2.91-3.30(1H, m), 6.98,
8.01(each 1H, d), 7.24, 7.74(each 2H,
d), 7.34(1H, s)
11-11
##STR200## 95 1.29-1.57(4H, m), 1.55-1.70(2H, m),
1.69-1.88(2H, m), 2.93, 3.44(each 1H,
d), 7.23(1H, t), 7.29(1H, s), 7.38,
7.58 (each 1H, d), 11.06(1H, br s)
11-12
##STR201## 94 1.23-1.65(6H, m), 2.60-2.77(1H, m),
2.84, 3.30(each 1H, d), 2.79-2.91(1H,
m), 3.82(3H, s), 6.90, 7.51(each 1H,
d), 7.24 (1H, s)
11-13
##STR202## 80 1.38-1.95(6H, m), 2.34, 3.82(each 3H,
s), 2.63(2H, t), 2.73, 2.92(each 1H,
d), 4.96(1H, s), 6.90, 7.77(each 1H,
d), 7.20, 7.73(each 2H, d), 7.22(1H,
__________________________________________________________________________
s)
TABLE 17
__________________________________________________________________________
Ref-
erence
Exam-
Structual
ple Formula Yield.sup.(%)
NMR (.delta..sub.ppm,
__________________________________________________________________________
CDCl.sub.3)
11-14
##STR203## 82 1.42-1.73(6H, m), 2.33, 3.83(each 3H,
s), 2.61(2H, d), 2.65- 2.74(2H, m),
2.84, 3.13(each 1H, d), 6.88,
7.65(each 1H, d), 7.18, 7.72(each 2H,
d), 7.17(1H, s)
11-15
##STR204## 53 1.30-1.58(6H, m), 2.60-2.83(6H, m),
3.75(3H, s), 6.78, 7.04 (each 1H, d),
6.94(1H, s)
__________________________________________________________________________
EXAMPLE I-1
4-Phenyl-4-[2-(1-imidazolyl)ethyl]isochroman hydrochloride
A mixture of synthesized 4-(2-iodoethyl)-4-phenylisochroman (0.6 g) and
imidazole (0.56 g) was heated in acetonitrile (15 ml) in the presence of
potassium carbonate (0.34 g) at 60.degree. C. with stirring for 4 days.
The reaction mixture was then poured in ice-water and the syrup separating
out was extracted with ether. The extract was washed with water, dried
over anhydrous sodium sulfate and concentrated to dryness. The residue was
purified by silica gel column chromatography (ethyl acetate-methanol=15:1)
and treated with 4NHCl/methanol to provide the title compound (0.32 g) as
non-crystalline powder.
EXAMPLE I-3
4-Phenyl-4-[2-(phthalimido)ethyl]isochroman
A mixture of synthesized 4-(2-iodoethyl)-4-phenylisochroman (0.5 g) and
potassium phthalimide (0.51 g) was heated in DMF (10 ml) at 60.degree. C.
with stirring for 14 hours. The reaction mixture was then poured in
ice-water and the syrup separating out was extracted with ethyl acetate.
The extract was washed with water, dried over anhydrous sodium sulfate and
concentrated to dryness. The residue was purified by silica gel column
chromatography and recrystallized from ethyl acetate-hexane to provide the
title compound (0.12 g) as colorless needless.
The following compounds I-2 and I-4.about.70 were synthesized in the same
manner as Example I-1 and I-3. Compounds of Examples I-1 through 1-70
EXAMPLE I-2
4-[2-(Morpholino)ethyl]-4-phenylisochroman hydrochloride
EXAMPLE I-4
4-[2-(Benzylamino)ethyl]-4-phenylisochroman hydrochloride
EXAMPLE I-5
4-[2-(m-Methoxybenzylamino)ethyl]-4-phenylisochroman hydrochloride
EXAMPLE I-6
4-[2-(4-Phenylpiperazin-1-yl)ethyl]-4-phenylisochroman dihydrochloride
EXAMPLE I-7
4-{2-[4-(p-Fluorophenyl)piperazin-1-yl]ethyl}-4phenylisochroman
hydrochloride
EXAMPLE I-8
4-{2-[4-(m-Chlorophenyl)piperazin-1-yl]ethyl}-4phenylisochroman
hydrochloride
EXAMPLE I-9
4-{2-[4-(2-Pyridyl)piperazin-1-yl]ethyl}-4-phenylisochroman dihydrochloride
EXAMPLE I-10
4-[2-(4-Benzylpiperazin-1-yl)ethyl]-4-phenylisochroman dihydrochloride
EXAMPLE I-11
4-[2-(4-Phenylpiperidino)ethyl]-4-phenylisochroman hydrochloride
EXAMPLE I-12
3,4-Dihydro-1'-[2-(4-phenylisochroman-4-yl)ethyl]spiro[naphthalene-2(1H),2'
-piperidine] hydrochloride
EXAMPLE I-13
3,4-Dihydro-6,7-dimethoxy-1'-[2-(4-phenylisochroman-4-yl)ethyl]spiro[naphth
alene-2(1H),2'-piperidine]hydrochloride
EXAMPLE I-14
4-[3-(1-Imidazolyl)propyl]-4-phenylisochroman hydrochloride
EXAMPLE I-15
4-[3-(1-Hexamethyleneimino)propyl]-4-phenylisochroman hydrochloride
EXAMPLE I-16
4-[3-(1,2,4,5-Tetrahydro-3H-benzazepin-3-yl)propyl]-4-phenylisochroman
hydrochloride
EXAMPLE I-17
4-(3-Anilinopropyl)-4-phenylisochroman hydrochloride
EXAMPLE I-18
4-[3-(Benzylamino)propyl]-4-phenylisochroman hydrochloride
EXAMPLE I-19
4-[3-(o-Fluorobenzylamino)propyl]-4phenylisochroman hydrochloride
EXAMPLE 1-20
4-[3-(o-Chlorobenzylamino)propyl]-4phenylisochroman hydrochloride
EXAMPLE I-21
4-[3-(N-Methylbenzylamino)propyl]-4phenylisochroman hydrochloride
EXAMPLE I-22
4-{3-[(2-Thienylmethyl)amino]propyl}-4-phenylisochroman hydrochloride
EXAMPLE I-23
4-[3-(2-picolylamino)propyl]-4-phenylisochroman dihydrochloride
EXAMPLE I-24
4-[3-(.beta.-Phenethylamino)propyl]-4-phenylisochroman hydrochloride
EXAMPLE I-25
4-[3-(3,4-Dimethoxyphenethylamino)propyl]-4phenylisochroman hydrochloride
EXAMPLE I-26
4-{3-[2-(2-Pyridyl)ethylamino]propyl}-4-phenylisochroman dihydrochloride
EXAMPLE I-27
4-{3-[2-(Morpholino)ethylamino]propyl}-4-phenylisochroman dihydrochloride
EXAMPLE I-28
4-[3-(2-Indanylamino)propyl]-4-phenylisochroman hydrochloride
EXAMPLE I-29
4-[3-(4-Phenylpiperazin-1-yl)propyl]-4-phenylisochroman dihydrochloride
EXAMPLE I-30
4-{3-[4-(p-Fluorophenyl)piperazin-1-yl]propyl}-4phenylisochroman
dihydrochloride
EXAMPLE I-31
4-{3-[4-(2-Benzothiazolyl)piperazin-1-yl]propyl}-4-phenylisochroman
dihydrochloride
EXAMPLE I-32
4-{3-[4-(3-Benzoisothiazolyl)piperazin-1yl]propyl}-4-phenylisochroman
hydrochloride
EXAMPLE I-33
4-[3-(4-Phenylpiperidino)propyl]-4-phenylisochroman hydrochloride
EXAMPLE I-34
4-{3-[4-(Piperidino)piperidino]propyl}-4-phenylisochroman dihydrochloride
EXAMPLE I-35
3,4-Dihydro-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[naphthalene-2(1H),2
'-piperidine]hydrochloride
EXAMPLE I-36
3,4-Dihydro-6-methoxy-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[naphthale
ne-2(1H),2'-piperidine] hydrochloride
EXAMPLE I-37
3,4-Dihydro-6,7-dimethoxy-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[napht
halene-2(1H),2'-piperidine]hydrochloride
EXAMPLE I-38
4-[3-(Benzylamino)propyl]-4-(p-fluorophenyl)isochroman hydrochloride
EXAMPLE I-39
4-{3-[4-(p-Fluorophenyl)piperazin-1-yl]propyl}-4-(p-fluorophenyl)isochroman
dihydrochloride
EXAMPLE I-40
4-[3-(Benzylamino)propyl]-4-(p-chlorophenyl)isochroman hydrochloride
EXAMPLE I-41
4-{3-[4-(p-Fluorophenyl)piperazin-1-yl]propyl}-4-(p-chlorophenyl)isochroman
dihydrochloride
EXAMPLE I-42
4-{3-[4-(2-Benzothiazolyl)piperazin-1-yl]propyl)-4-(p-chlorophenyl)isochrom
an trihydrochloride
EXAMPLE I-43
4-[3-(Benzylamino)propyl]-7-chloro-4-(p-chlorophenyl)isochroman
hydrochloride
EXAMPLE I-44
4-{3-[4-(p-Fluorophenyl)piperazin-1-yl]propyl}-7-chloro-4-(p-chlorophenyl)i
sochroman dihydrochloride
EXAMPLE I-45
Methyl .alpha.-[3-(4-phenylisochroman-4-yl)propylamino]-m-toluate
hydrochloride
EXAMPLE I-46
4-[3-(m-Methylbenzylamino)propyl]-4-phenylisochroman hydrochloride
EXAMPLE I-47
6,7-Dihydro-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[4-oxobenzo(b)thioph
ene-5(4H),2'-piperidine]hydrochloride
EXAMPLE I-48
3,4-Dihydro-6-methoxy-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[1-oxonaph
thalene-2-(1H),2'-piperidine]hydrochloride
EXAMPLE I-49
3,4-Dihydro-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[1-oxonaphthalene-2(
1H),2'-piperidine]hydrochloride
EXAMPLE I-50
3,4-Dihydro-6,7-dimethoxy-1'-{3-[4-(p-fluorophenyl)isochroman-4-yl]propyl}s
piro[naphthalene-2(1H),2'-piperidine] hydrochloride
EXAMPLE I-51
4-Phenyl-4-{3-[1-(1,2,3,4-tetrahydronaphthylamino)]propyl]isochroman
hydrochloride
EXAMPLE I-52
3,4-Dihydro-6,7-dimethoxy-1'-[4-(4-phenylisochroman-4-yl)butyl]spiro[naphth
alene-2(1H),2'-piperidine]hydrochloride
EXAMPLE I-53
6,7-Dihydro-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro[benzo[b]thiophene-5
(4H),2'-piperidine hydrochloride
EXAMPLE I-54
4-{3-[N-Methyl-N-2-(3,4methylenedioxyphenyloxy)ethyl)amino]propyl}-4phenyli
sochroman hydrochloride
EXAMPLE I-55
4-{3-[(2-Biphenylmethyl)amino]propyl}-4-phenylisochroman hydrochloride
EXAMPLE I-56
4-{3-[3,4-Dimethoxyphenyl)ureido]propyl}-4-phenylisochroman
EXAMPLE I-57
1'-[3-(4-Phenylisochroman-4-yl)propyl]spiro{1H-benz[cd]indole-4(3H,5H),
2'-piperidine}-5-one hydrochloride
EXAMPLE I-58
6-Methoxy-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro{1H-benz[cd]indole-4(3
H,5H), 2'-piperidine}-5-one hydrochloride
EXAMPLE I-59
6-Methoxy-1'-[3-(4-phenylisochroman-4-yl)propyl]spiro{1H-benz[cd]indole-4(3
H,5H), 2'-piperizin}hydrochloride
EXAMPLE I-60
4-[3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-ylpropyl]-4-phenylisoch
roman hydrochloride
EXAMPLE 1-61
4-{3-[4-(2-Oxoindolin-3-yl)piperidino]propyl}-4-phenylisochroman
EXAMPLE I-62
4-[3-(Benzylamino)propyl]-4-(2-pyridyl)isochroman hydrochloride
EXAMPLE I-63
4-[3-(Isoindolin-2-yl)propyl]-4-phenylisochroman hydrochloride
EXAMPLE I-64
4-[3-Benzylamino)propyl]-4-(benzothiazolyl)isochroman hydrochloride
EXAMPLE I-65
3,4-dihydro-1'-[3-(6,7-dimethoxy-4-phenylisochroman-4-yl)propyl]spiro[napht
halene-2(1H),2'-piperidine]hydrochloride
EXAMPLE I-66
4-{3-[(2-naphthylmethyl)amino]propyl}-4-phenylisochroman hydrochloride
EXAMPLE I-67
4-Phenyl-4-{3-[3-(3,4,5-trimethoxyphenyl)propionylamino]propyl}isochroman
EXAMPLE I-68
4-[3-(8,9-dimethoxy-6,6-dimethyl-3-benzazocin-3-yl)propyl]-4-phenylisochrom
an hydrochloride
EXAMPLE I-69
4-[3-(N-Acetyl-benzylamino)propyl]-4-(benzothiazolyl)isochroman
EXAMPLE I-70
4-{3-[2-(1,2,3,4-tetrahydro-7-methoxynaphthyl)
amino]propyl}-4-phenylisochroman hydrochloride
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Tables 18, 19, 20, 21, 22, 23, 24, 25,
26, 27 and 28.
TABLE 18
-
##STR205##
Elemental Analysis
[Found/(Calculated)]
Example R' R.degree. Ar m x Melting Point (.degree.C.) NMR (.delta..sub.
ppm, CDCl.sub.3) CHN
I-1
##STR206##
H
##STR207##
2 1 Noncrystal-line powder 2.58(1H, ddd), 2.82(1H, ddd), 3.73(1H, ddd),
3.89(1H, d), 4.00(1H, d),4.22(1H, ddd), 4.91(2H, s), 6.70-7.40(12H, m).
C.sub.20 H.sub.20 N.sub.2 O.HCl. 2/5H.sub.2 O69.19 6.37 8.38(69.01 6.37
8.38)
I-2
##STR208##
H
##STR209##
2 1 187-190 2.19-2.55(8H, m), 3.69(4H, t), 3.92(2H, s), 4.86(2H, s),
6.93-7.07(2H,m), 7.10-7.34(7H, m) C.sub.21 H.sub.25 NO.sub.2.HCl.
3/10H.sub.2 O69.07 7.51 3.79(69.05 7.34
3.83)
I-3
##STR210##
H
##STR211##
2 -- 162-164 2.45-2.70(2H, m), 3.57-3.91(2H, m),4.00(2H, q), 4.90(2H,
s), 7.00-7.11(2H, m), 7.12-7.39(6H, m), 7.63-7.90(5H, m) C.sub.25
H.sub.21 NO.sub.3 77.72 5.42 3.87(78.31 5.52
3.65)
I-4
##STR212##
H
##STR213##
2 1 182-185 1.41(1H, br s), 2.29-2.82(4H, m),3.70(2H, s), 3.91(2H, q),
4.84(2H,s), 6.92-7.34(14H, m) C.sub.24 H.sub.25 NO.HCl75.82 6.97
3.62(75.87 6.90
3.69)
I-5
##STR214##
H
##STR215##
2 1 165-167 1.42(1H, br s), 2.29-2.81(4H, m),3.69(2H, s), 3.78(3H, s),
3.91(2H,q), 4.85(2H, s), 6.74-7.30(13H, m) C.sub.25 H.sub.27
NO.sub.2.HCl. 1/5H.sub.2 O72.44 6.94 3.53(72.61 6.92
3.39)
I-6
##STR216##
H
##STR217##
2 2 238-240 2.23-2.61(8H, m), 3.19(4H, t), 3.94(2H, s), 4.87(2H, s),
6.79-7.08(5H,m), 7.09-7.30(9H, m) C.sub.27 H.sub.30 N.sub.2 O.2HCl68.53
6.98 5.81(68.78 6.84
5.94)
I-7
##STR218##
H
##STR219##
2 1 234-237 2.25-2.63(8H, m), 3.11(4H, t), 3.95(2H, s), 4.88(2H, s),
6.82-7.26(13H, m) C.sub.27 H.sub.30 FN.sub.2 O.HCl. 7/5Hhd 2O67.94 6.60
5.85(67.81 6.91
5.86)
TABLE 19
- Elemental Analysis
[Found/Calculated)]
Example R' R.degree. Ar m x Melting Point (.degree.C.) NMR (.delta..sub.
ppm, CDCl.sub.3) CHN
I-8
##STR220##
H
##STR221##
2 1 221-224 2.23-2.52(4H, m), 2.55(4H, t), 3.18(4H, t), 3.94(2H, s),
4.87(2H, s),6.71-6.89(3H, m), 6.95-7.36(10H, m) C.sub.27 H.sub.29
ClN.sub.2 O.HCl68.97 6.47 5.86(69.08 6.44
5.97)
I-9
##STR222##
H
##STR223##
2 2 195-198 2.22-2.60(8H, m), 3.53(4H, t), 3.94(2H, s), 4.87(2H, s),
6.59(1H, d),6.62(1H, d), 6.95-7.07(2H, m),7.08-7.34(7H, m), 7.40-7.50(1H,
m),8.15-8.19(1H, m) C.sub.26 H.sub.29 N.sub.3 O.2HCl. 1/2H.sub.2 O65.12
6.88 8.95(64.86 6.70
8.73)
I-10
##STR224##
H
##STR225##
2 2 230-232 2.18-2.58(12H, m), 3.49(2H, s), 3.93(2H, s), 4.85(2H, s),
6.93-7.31(14H,m), C.sub.28 H.sub.32 N.sub.2 O.2HCl69.04 7.20 5.92(69.27
7.06
5.77)
I-11
##STR226##
H
##STR227##
2 1 222-226 1.71-2.09(6H, m), 2.21-2.60(5H, m),2.99-3.10(2H, m),
3.95(2H, s), 4.87(2H, s), 6.97-7.09(2H, m), 7.10-7.35(12H, m) C.sub.28
H.sub.31 NO.HCl. 1/5H.sub.2 O76.82 7.37 3.25(76.85 7.46
3.20)
I-12
##STR228##
H
##STR229##
2 1 Noncrystal-line powder 1.40-1.80(10H, m), 2.10-2.80(10H, m)3.91(2H,
s), 4.87(2H, s), 6.90-7.30(13H, m). C.sub.31 H.sub.35 NO.HCl.2H.sub.2
O72.81 7.62 2.38(72.99 7.90
2.75)
I-13
##STR230##
H
##STR231##
2 1 Noncrystal-line powder 1.35-1.82(8H, m), 2.10-2.72(10H, m),3.80(3H,
s), 3.82(3H, s), 3.92(2H,s), 4.82(2H, s), 6.48(1H, d), 6.54(1H, d),
6.91-7.30(9H, m) C.sub.33 H.sub.39 NO.sub.3.HCl. 5/2H.sub.2 O68.44 7.83
2.42(68.36 7.21
2.51)
I-14
##STR232##
H
##STR233##
3 1 Noncrystal-line powder 1.60-2.30(4H, m), 3.85(2H, s), 3.89(2H, t),
4.87(2H, s), 6.85(2H, m),7.00-7.30(9H, m), 7.43(1H, s). C.sub.21
H.sub.22 N.sub.2 O.HCl. 5/4H.sub.2 O67.11 6.66 7.46(66.83 6.81
7.42)
TABLE 20
- Elemental Analysis
[Found/(Calculated)]
Example R' R.degree. Ar m x Melting Point (.degree.C.) NMR (.delta..sub.
ppm, CDCl.sub.3) CHN
1-15
##STR234##
H
##STR235##
3 1 Noncrystal-line powder 1.40-1.70(10H, m), 2.17(2H, dt),2.44(2H, t),
2.53(4H, br s), 3.92(2H, d), 4.87(2H, s), 6.90-7.30(9H, m) C.sub.24
H.sub.31 NO.HCl.2H.sub.2 O68.09 8.08 3.30(68.31 8.60
3.32)
1-16
##STR236##
H
##STR237##
3 1 Noncrystal-line powder 1.40-1.60(2H, m), 2.20(2H, dt), 2.46(2H, t),
2.56(4H, dd), 2.89(4H, dd),3.92(2H, s), 4.88(2H, s), 6.90- C.sub.28
H.sub.31 NO.HCl. 3/4H.sub.2 O75.33 7.45 3.13(75.14 7.55
3.13)
1-17
##STR238##
H
##STR239##
3 1 Noncrystal-line powder 1.50-1.80(2H, m), 2.29(2H, m),3.10(2H, t),
3.92(2H, s), 4.88(2H, s), 6.50-7.30(14H, m). C.sub.24 H.sub.25
NO.HCl.H.sub.2 O72.18 7.09 3.22(72.44 7.09
3.52)
I-18
##STR240##
H
##STR241##
3 1 Noncrystal-line powder 1.40-1.60(2H, m), 2.22(2H, dt), 2.63(2H, t),
3.74(2H, s), 3.91(2H, s),4.87(2H, s), 6.90-7.30(14H, m). C.sub.25
H.sub.27 NO.HCl. 1/4H.sub.2 O75.54 7.21 3.31(75.35 7.21
3.52)
I-19
##STR242##
H
##STR243##
3 1 Noncrystal-line powder 1.39-1.62(2H, m), 2.09-2.37(2H, m),2.62(2H,
t), 3.79(2H, s), 3.90(2H,s), 4.86(2H, s), 6.93-7.33(13H, m) C.sub.25
H.sub.26 FNO.HCl72.59 6.77 3.50(72.89 6.61
3.40)
I-20
##STR244##
H
##STR245##
3 1 Noncrystal-line powder 1.40-1.60(2H, m), 2.23(2H, dt), 2.62(2H, t),
3.83(2H, s), 3.91(2H, s),4.87(2H, s), 6.90-7.40(14H, m). C.sub.25
H.sub.26 ClNO.HCl. 1/4H.sub.2 O69.40 6.30 3.16(69.36 6.30
3.16)
I-21
##STR246##
H
##STR247##
3 1 Noncrystal-line powder 1.40-1.60(2H, m), 2.12(3H, s), 2.20(2H, dt),
2.36(2H, t), 3.42(2H, s),3.91(2H, s), 4.86(2H, s), 6.90-7.30(14H, m).
C.sub.26 H.sub.29 NO.HCl.H.sub.2 O73.37 7.50 3.24(73.31 7.57 3.29)
I-22
##STR248##
H
##STR249##
3 1 Noncrystal-line powder 1.40-1.60(2H, m), 2.23(2H, dt), 2.66(2H, t),
3.91(2H, s), 3.94(2H, s),4.87(2H, s), 6.80-7.30(12H, m). C.sub.23
H.sub.25 NOS.HCl. 3/5H.sub.2 O67.13 6.59 3.15(67.24 6.67
3.41)
TABLE 21
__________________________________________________________________________
Melting
Example
R' R.sup.0
Ar m x Point (.degree.C.)
__________________________________________________________________________
I-23
##STR250## H
##STR251##
3 2 Noncrystal- line powder
I-24
##STR252## H
##STR253##
3 1 Noncrystal- line powder
I-25
##STR254## H
##STR255##
3 1 Noncrystal- line powder
I-26
##STR256## H
##STR257##
3 2 Noncrystal- line powder
I-27
##STR258## H
##STR259##
3 2 Noncrystal- line powder
I-28
##STR260## H
##STR261##
3 1 Noncrystal- line powder
__________________________________________________________________________
Elemental Analysis
[Found/(Calculated)]
Example NMR (.delta..sub.ppm, CDCl.sub.3)
C H N
__________________________________________________________________________
I-23 1.55(2H, m), 1.24(2H, dt), 2.67(2H,
C.sub.24 H.sub.26 N.sub.2 O.2HCl. 1/2H.sub.2
O
t), 3.87(2H, s), 3.91(2H, s), 4.86
65.59 6.37 6.52
(2H, s), 6.90-7.30(11H, m), 7.63(1H,
(65.45 6.63 6.36)
dt), 8.54(1H, m).
I-24 1.35-1.63(2H, m), 2.04-2.32(2H, m),
C.sub.26 H.sub.29 NO.HCl. 1/2H.sub.2 O
2.61(2H, t), 2.72-2.90(4H, m), 3.89
75.03 7.55 3.56
(2H, q), 4.86(2H, s), 6.92-7.35(14H,
(74.89 7.49 3.36)
m)
I-25 1.40-1.60(2H, m), 2.18(2H, dt),
C.sub.28 H.sub.33 NO.sub.3.HCl.H.sub.2 O
2.63(2H, t), 2.70-2.90(4H, m), 3.85
69.43 7.39 2.98
(s, 6H), 3.90(2H, s), 4.89(2H, s)
(69.19 7.47 2.88)
6.70-7.30(12H, m).
I-26 1.49(2H, m), 2.19(2H, dt), 2.64
C.sub.25 H.sub.28 N.sub.2 O.2HCl. 3/2H.sub.2
O
(2H, t), 2.97(4H, t), 3.90(2H, s),
61.88 6.73 5.98
4.86(2H, s), 6.90-7.30(11H, m),
(62.16 6.58 6.30)
7.59(1H, dt), 8.51(1H dt).
I-27 1.40-1.60(2H, m), 2.21(2H, dt), 2.44
C.sub.24 H.sub.32 N.sub.2 O.sub.2.2HCl.
1/2H.sub.2 O
(6H, m), 2.63(4H, m), 3.68(4H, t),
61.94 7.90 6.24
3.91(2H, s), 4.87(2H, s), 6.90-7.30
(62.33 7.63 6.06)
(2H, m).
I-28 1.40-1.60(2H, m), 2.22(2H, dt), 2.60-
C.sub.27 H.sub.29 NO.HCl. 1/2H.sub.2 O
2.80(4H, m), 3.23(2H, dd), 3.58(1H,
75.28 7.46 3.10
m), 3.91(2H, s), 4.86(2H, s), 6.90-
(75.59 7.28 3.26)
7.30(13H, m).
__________________________________________________________________________
TABLE 22
__________________________________________________________________________
Melting
Example
R' R.sup.0
Ar m n Point (.degree.C.)
__________________________________________________________________________
I-29
##STR262## H
##STR263##
3 2 119-121
I-30
##STR264## H
##STR265##
3 2 122-124
I-31
##STR266## H
##STR267##
3 2 152-154
I-32
##STR268## H
##STR269##
3 1 222-227
I-33
##STR270## H
##STR271##
3 1 Noncrystal- line powder
I-34
##STR272## H
##STR273##
3 2 265-267
I-35
##STR274## H
##STR275##
3 1 Noncrystal- line powder
__________________________________________________________________________
Elemental Analysis
[Found/(Calculated)]
Example NMR (.delta..sub.ppm, CDCl.sub.3)
C N H
__________________________________________________________________________
I-29 1.40-1.60(2H, m), 2.23(2H, m),
C.sub.28 H.sub.32 N.sub.2 O.2HCl
2.39(2H, t), 2.54(4H, t), 3.18(4H,
69.27 7.06 5.77
t), 3.93(2H, s), 4.88(2H, s), 6.80-
(69.27 7.05 5.96)
7.30(14H, m).
I-30 1.40-1.60(2H, m), 2.23(2H, m),
C.sub.28 H.sub.31 FN.sub.2 O.2HCl. 1/2H.sub.2
O
2.39(2H, t), 2.53(4H, dd), 3.09(4H,
65.74 6.51 5.67
t), 3.92(2H, s), 4.88(2H, s), 6.80-
(65.62 6.69 5.47)
7.30(13H, m).
I-31 1.40-1.70(2H, m), 2.22(2H, dt),
C.sub.29 H.sub.31 N.sub.3 OS.2HCl. 4/5H.sub.2
O
2.39(2H, t), 2.50(4H, t), 3.63(4H,
62.57 6.20 7.87
t), 2.93(2H, s), 4.89(2H, s), 6.90-
(62.53 6.26 7.54)
7.40(14H, m).
I-32 1.40-1.70(2H, m), 2.25(2H, dt), 2.42
C.sub.29 H.sub.31 N.sub.3 OS.HCl. 3/4H.sub.2
O
(2H, t), 2.60(4H, dd), 3.54(4H, t),
67.08 6.32 8.39
3.93(2H, s), 4.88(2H, s), 7.00-7.50
(67.03 6.69 8.08)
(11H, m), 7.80(1H, d), 7.99(1H, d).
I-33 1.40-2.50(13H, m), 3.98(2H, br d),
C.sub.29 H.sub.33 NO.HCl. 9/10H.sub.2 O
3.93(2H, s), 4.88(2H, s), 7.00-
75.34 7.58 3.30
7.30(14H, m). (75.02 7.77 3.02)
I-34 1.40-2.40(23H, m), 2.56(4H, t),
C.sub.28 H.sub.38 N.sub.2 O.2HCl
2.92(2H, br d), 3.91(2H, s), 4.87
67.19 8.38 5.57
(2H, s), 6.90-7.30(9H, m).-
(66.80 8.62 5.99)
I-35 1.30-2.00(10H, m), 2.10-2.90(10H, m)
C.sub.32 H.sub.37 NO.HCl. 7/4H.sub.2 O
3.91(2H, dd), 4.87(2H, s), 6.90-7.30
73.99 8.00 2.32
(13H, m). (73.96) 8.05 2.69)
__________________________________________________________________________
TABLE 23
__________________________________________________________________________
Melting
Example
R' R.sup.0
Ar m n Point (.degree.C.)
__________________________________________________________________________
I-36
##STR276## H
##STR277##
3 1 Noncrystal- line powder
I-37
##STR278## H
##STR279##
3 1 Noncrystal- line powder
I-38
##STR280## H
##STR281##
3 1 Noncrystal- line powder
I-39
##STR282## H
##STR283##
3 2 112-115
I-40
##STR284## H
##STR285##
3 1 Noncrystal- line powder
I-41
##STR286## H
##STR287##
3 2 139-142
I-42
##STR288## H
##STR289##
3 3 145-147
__________________________________________________________________________
Elemental Analysis
[Found/(Calculated)]
Example NMR (.delta..sub.ppm, CDCl.sub.3)
C N H
__________________________________________________________________________
I-36 1.30-1.90(10H, m), 2.10-2.80(10H, m),
C.sub.33 H.sub.39 NO.sub.2.HCl. 3/4H.sub.2 O
3.77(3H, s), 3.91(1H, d), 3.92(1H,
74.62 7.66 2.86
d), 4.97(2H, s), 6.64(2H, m), 6.90-
(74.55 7.87 2.63)
7.30(10H, m).
I-37 1.30-2.00(10H, m), 2.10-2.90(10H, m),
C.sub.34 H.sub.41 NO.sub.3.HCl. 9/10H.sub.2 O
3.83(6Hx5.7, s), 3.85(6Hx2/7, s),
72.76 7.57 2.61
3.91(2H, d), 4.88(2H, s), 6.55(2Hx
(72.35 7.82 2.48)
2/7, s), 6.58(2Hx5/7, s), 6.90-7.30
(9H, m).
I-38 1.40-1.60(2H, m), 2.19(2H, dt), 2.62
C.sub.25 H.sub.26 FNO.HCl. 3/4H.sub.2 O
(2H, t), 3.74(2H, s), 3.87(2H, s),
70.87 6.80 3.17
4.85(2H, s), 6.90-7.30(12H, m).
(70.57 6.75 3.29)
I-39 1.40-1.60(2H, m), 2.20(2H, m),
C.sub.28 H.sub.30 FN.sub.2 O.2HCl
2.41(2H, t), 2.53(4H, t), 3.09(4H,
62.75 6.69 5.18
t), 3.89(2H, s), 4.87(2H, s), 6.80-
(62.54 6.34 5.21)
7.30(12H, m).
I-40 1.30-1.60(2H, m), 2.18(2H, dt), 2.62
C.sub.25 H.sub.26 ClNO.HCl.H.sub.2 O
2H, t), 3.73(2H, s), 3.87(2H, s),
67.12 6.15 3.11
4.85(2H, s), 6.90-7.30(13H, m).
(67.25 6.55 3.14)
I-41 1.40-1.60(2H, m), 2.20(2H, m),
C.sub.28 H.sub.30 FN.sub.2 O.2HCl. 1/2H.sub.2
O
2.37(2H, t), 2.53(4H, t), 3.10(4H,
61.74 6.17 5.01
t), 3.89(2H, s), 4.87(2H, s), 6.80-
(61.37 6.25 5.11)
7.30(12H, m).
I-42 1.30-1.60(2H, m), 2.21(2H, m),
C.sub.29 H.sub.30 ClN.sub.2 OS.3HCl.
1/4H.sub.2
2.37(2H, t), 2.49(4H, t), 3.62(4H,
56.28 5.73 6.70
t), 3.89(2H, s), 4.87(2H, s), 6.90-
(56.36) 5.46 6.80)
7.40(10H, m), 7.57(2H, t).
__________________________________________________________________________
TABLE 24
__________________________________________________________________________
Melting
Example
R' R.sup.0
Ar m x Point (.degree.C.)
__________________________________________________________________________
I-43
##STR290## 7-Cl
##STR291##
3 1 Noncrystal- line powder
I-44
##STR292## 7-Cl
##STR293##
3 2 122-125
I-45
##STR294## H
##STR295##
3 1 71-76
I-46
##STR296## H
##STR297##
3 1 Noncrystal- line powder
I-47
##STR298## H
##STR299##
3 1 Noncrystal- line powder
I-48
##STR300## H
##STR301##
3 1 Noncrystal- line powder
__________________________________________________________________________
Elemental Analysis
[Found/(Calculated)]
Example NMR (.delta..sub.ppm, CDCl.sub.3)
C N H
__________________________________________________________________________
I-43 1.30-1.60(2H, m), 2.16(2H, dt), 2.62
C.sub.25 H.sub.25 Cl.sub.2 NO.HCl.H.sub.2 O
(2H, t), 3.74(2H, s), 3.84(2H, s),
62.73 5.82 2.69
4.80(2H, s), 6.85-7.30(12H, m).
(62.45 5.87 2.91)
I-44 1.30-1.60(2H, m), 2.18(2H, m),
C.sub.28 H.sub.29 Cl.sub.2 FN.sub.2 O.2HCl
2.37(2H, t), 2.53(4H, t), 3.10(4H,
58.68 5.74 4.67
t), 3.86(2H, s), 4.82(2H, s), 6.80-
(58.76 5.46 4.89)
7.30(11H, m).
I-45 1.40-1.62(2H, m), 2.08-2.37(2H, m),
C.sub.27 H.sub.29 NO.sub.3.HCl. 4/5H.sub.2 O
2.62(2H, t), 3.78, 3.90, 4.86(2H each,
69.47 6.56 3.01
s), 3.90(3H, s), 6.96, 7.02(1H each,
(69.53 6.83 3.00)
dd), 7.06-7.30(6H, m), 7.37(1H, t),
7.49, 7.91(1H each, dt), 7.96(1H, s)
I-46 1.50(2H, m), 2.21(2H, m), 2.33(3H,
C.sub.26 H.sub.29 NO.HCl.0.8H.sub.2 O
(2H, t), 3.74(2H, s), 3.84(2H, s),
73.83 7.58 3.32
4.80(2H, s), 6.85-7.30(12H, m)
(73.93 7.54 3.32)
I-47 1.40-1.85(8H, m), 2.10-2.60(7H, m),
C.sub.30 H.sub.33 NO.sub.2 S.HCl.1.5H.sub.2 O
2.90-3.20(3H, m), 3.91(2H, s), 4.85
67.20 7.04 2.41
(2H, s), 6.95-7.50(11H, m).
(67.33 6.97 2.41)
I-48 1.34-1.84(4H, m), 1.95-2.15(3H, m),
C.sub.33 H.sub.37 NO.sub.3.HCl.1.2H.sub.2 O
2.20-2.65(4H, m), 2.82-3.11(3H, m),
70.57 7.13 2.74
3.84(3H, s), 3.88(3H, s), 4.84(2H,
(70.89 7.39 2.51)
s), 6.65(1H, d), 6.83(1H, dd), 6.92-
7.04(2H, m), 7.06-7.31(7H, m),
8.01(1H, dd).
__________________________________________________________________________
TABLE 25
__________________________________________________________________________
Melting
Example
R' R.sup.0
Ar m x Point (.degree.C.)
__________________________________________________________________________
I-49
##STR302## H
##STR303##
3 1 Noncrystal- line powder
I-50
##STR304## H
##STR305##
3 1 Noncrystal- line powder
I-51
##STR306## H
##STR307##
3 1 Noncrystal- line powder
I-52
##STR308## H
##STR309##
4 1 Noncrystal- line powder
I-53
##STR310## H
##STR311##
3 1 Noncrystal- line powder
__________________________________________________________________________
Elemental Analysis
[Found/(Calculated)]
Example NMR (.delta..sub.ppm, CDCl.sub.3)
C N H
__________________________________________________________________________
I-49 1.47-1.87(8H, m), 1.96-2.14(3H, m),
C.sub.32 H.sub.35 NO.sub.2.HCl.1.5H.sub.2 O
2.20-2.68(4H, m), 2.86-3.08(3H, m),
72.16 7.17 2.81
3.87(2H, s), 4.84(2H, s), 6.92-7.04
(72.64 7.43 2.65)
(2H, m), 7.08-7.36(8H, m), 7.44(2H,
dt), 7.99-8.06(1H, m).
I-50 1.30-2.00(10H, m), 2.10-2.90(10H,
C.sub.34 H.sub.40 FNO.sub.3.HCl.2.5H.sub.2 O
m), 3.80-3.90(8H, m), 4.87(2H, s),
67.07 7.33 2.14
6.56-6.58(2H, m), 6.90-7.30(8H, m).
(66.82 7.59 2.29)
I-51 1.50(2H, m), 1.60-2.00(4H, m), 2.10-
C.sub.28 H.sub.31 NO.HCl.H.sub.2 O
2.40(2H, m), 2.60-2.80(4H, m),
74.73 7.40 2.97
3.70(1H, t), 3.92(2H, s), 4.87(2H,
(74.40 7.58 3.10)
s), 6.95-7.35(13H, m).
I-52 1.19-1.38(1H, m), 1.37-1.92(11H, m),
C.sub.35 H.sub.43 NO.sub.3.HCl.H.sub.2 O
2.08-2.37(4H, m), 2.51-2.85(6H, m),
72.48 7.87 2.56
3.83(6H, s), 3.90, 4.87(2H each, s),
(72.45 7.99 2.41)
6.54, 6.56(1H each, s), 6.94-7.34
(9H, m)
I-53 1.35-2.95(15H, m), 3.91(2H, d),
C.sub.30 H.sub.35 NOS.HCl.H.sub.2 O
4.88('2H, s), 6.91(1H, q),
70.18 7.17 2.56
6.98-7.50(10H, m) (70.36 7.48 2.78)
__________________________________________________________________________
TABLE 26
__________________________________________________________________________
(%) Melting
Example
R' R.sup.0
Ar m x Yield
Point (.degree.C.)
__________________________________________________________________________
I-54
##STR312## H
##STR313##
3 1 69 Noncrystal- line powder
I-55
##STR314##
##STR315##
3 1 66 Noncrystal- line powder
I-56
##STR316## H
##STR317##
3 --
50 69-74
I-57
##STR318## H
##STR319##
3 1 79 183-188
I-58
##STR320## H
##STR321##
3 1 83 174-179
I-59
##STR322## H
##STR323##
3 1 69 175-180
__________________________________________________________________________
Elemental Analysis
[Found/(Calculated)]
Example
NMR (.delta..sub.ppm, CDCl.sub.3)
C N H
__________________________________________________________________________
I-54 1.39-1.61(2H, m), 2.14-2.26(2H, m), 2.26(3H, s),
C.sub.26 H.sub.31 NO.sub.4.HCl.H.sub.2 O
2.43, 2.70(2H each, t), 3.91, 4.87(2H each, s), 3.95
67.27 6.84 3.58
(2H, t), 5.90(2H, s), 6.29(1H, dd), 6.47, 6.68
(67.26 6.85 2.80)
(1H each, d), 6.93-7.32(9H, m)
I-55 1.24-1.50(2H, m), 1.97-2.24(2H, m), 2.45(2H, t),
C.sub.31 H.sub.31 NO.HCl. 1/2H.sub.2 O
3.69, 4.84(2H each, s), 3.86(2H, q), 6.91(1H, dd),
77.47 6.79 3.16
6.99-7.44(17H, m) (77.72 6.94 2.92)
I-56 1.36-1.65(2H, m), 2.05-2.34(2H, m), 3.21(2H, q),
C.sub.27 H.sub.30 N.sub.2 O.sub.4
3.84(3H each, s), 3.87(2H, s), 4.83(2H, s), 4.84(1H,
72.79 6.77 6.10
br t), 6.47(1H, br s), 6.66(1H, dd), 6.77(1H, d),
(72.62 6.77 6.27)
6.87-7.31(10H, m).
I-57 1.35-1.79(8H, m), 2.00-2.30(2H, m), 2.33-2.72(3H,
C.sub.33 H.sub.34 N.sub.2 O.sub.2.HCl.H.su
b.2 O
2.99-3.16(1H, m), 3.30, 4.85(2H each, s), 3.93(2H,
72.61 6.87 4.95
q), 6.97-7.31(11H, m), 7.50(1H, d), 7.62(1H, ddd),
(72.71 6.84 5.14)
8.47(1H, br s),
I-58 1.30-1.80(7H, m), 2.04-2.20(2H, m), 2.41-2.83(4H,
C.sub.34 H.sub.36 N.sub.2 O.sub.3.HCl.
3/2.sub.2 O
3.05(1H, dd), 3.07-3.30(1H, m), 3.34(1H, d), 3.90,
70.10 6.91 4.85
4.83(2H each, s), 3.94(3H, s), 6.85(1H, d), 6.94-7.30
(69.91 6.90 4.80)
(10H, m), 7.43(1H, dd), 8.42(1H, br s)
I-59 1.30-1.66(9H, m), 2.10-2.34(2H, m), 2.37-2.79(5H,
C.sub.34 H.sub.38 N.sub.2 O.sub.2.HCl.
1/10H.sub.2 O
2.80-3.19(2H, m), 3.85(3H, s), 3.92, 4.88(2H each,
73.40 7.28 4.93
6.80-6.87(2H, m), 6.95-7.31(10H, m), 7.66(1H, br
(73.48 7.33 5.04)
__________________________________________________________________________
TABLE 27
__________________________________________________________________________
(%) Melting
Example
R' R.sup.0
Ar m x Yield
Point (.degree.C.)
__________________________________________________________________________
I-60
##STR324## H
##STR325##
3 1 67 Noncrystal- line powder
I-61
##STR326## H
##STR327##
3 --
44 Noncrystal- line powder
I-62
##STR328## H
##STR329##
3 2 52 117-122
I-63
##STR330## H
##STR331##
3 1 51 Noncrystal- line powder
I-64
##STR332## H
##STR333##
3 1 70 Noncrystal- line powder
I-65
##STR334## 6,7- (OMe).sub.2
##STR335##
3 1 57 Noncrystal- line powder
I-66
##STR336## H
##STR337##
3 1 80 Noncrystal- line powder
I-67
##STR338## H
##STR339##
3 --
47 Oil
__________________________________________________________________________
Elemental Analysis
[Found/(Calculated)]
Example
NMR (.delta..sub.ppm, CDCl.sub.3)
C N H
__________________________________________________________________________
I-60 1.52-1.72(2H, m), 2.20-2.35(2H, m), 2.49, 2.64, 2.80
C.sub.29 H.sub.33 NO.sub.3.HCl.
3/2H.sub.2 O
(2H each, t), 3.48, 3.93, 4.88(2H each, s), 3.82,
68.90 7.17 2.65
(3H each, s), 6.49, 6.58(1H each, s), 6.99-7.33(9H,
(68.69 7.35 2.76)
I-61 1.31-1.60(4H, m), 1.62-2.00(5H, m), 2.01-2.33(4H,
C.sub.31 H.sub.34 N.sub.2 O.sub.2.3.5H.sub
.2 O
2.72-2.98(2H, m), 3.37(1H, d), 3.88(2H, q), 4.84(2H,
77.93 7.26 6.20
s), 6.79-7.33(13H, m), 8.42(1H, br s)
(77.99 7.43 5.87)
I-62 1.30-1.63(2H, m), 2.12-2.51(2H, m), 2.63(2H, t),
C.sub.24 H.sub.26 N.sub.2 O.2HCl.
6/5H.sub.2 O
3.73, 4.85(2H each, s), 3.96, 4.29(1H each, d), 7.01-
63.82 6.91 5.53
7.13(3H, m), 7.15-7.40(8H, m), 7.50(1H, dt), 8.59
(63.63 6.76 6.18)
(1H, ddd)
I-63 1.43-1.76(2H, m), 2.18-2.43(2H, m), 2.71(2H, t),
C.sub.26 H.sub.27 NO.HCl. 6/5H.sub.2 O
3.85(4H, s), 3.94, 4.88(2H each, s), 6.98-7.07(2H,
73.13 6.90 3.17
m), 7.10-7.31(11H, m) (73.03 7.17 3.28)
I-64 1.40-1.75(2H, m), 2.30-2.62(2H, m), 2.67(2H, t),
C.sub.26 H.sub.26 N.sub.2 OS.HCl.
3/5H.sub.2 O
3.75, 4.89(2H each, s), 4.08, 4.42(1H each, d),
67.58 6.22 6.02
7.02-7.09(1H, m), 7.19-7.47(10H, m), 7.75, 8.00
(67.62 6.15 6.07)
(1H each, dd)
I-65 1.30-2.00(10H, m), 2.05-2.93(10H, m), 3.69(3H, s),
C.sub.34 H.sub.41 NO.sub.3.HCl.
5/2H.sub.2 O
3.86(5H, s), 4.79(2H, s), 6.45(1H, s), 6.50(1H, s),
68.70 7.79 2.23
7.00-7.34(9H, m) (68.84 7.99 2.36)
I-66 1.40-1.65(2H, m), 2.09-2.37(2H, m), 2.73(2H, t),
C.sub.26 H.sub.29 NO.HCl. 5/2H.sub.2 O
(2H, s), 4.19(2H, s), 4.86(2H, s), 6.92-7.33(9H,
75.45 6.73 2.97
7.38-7.55(4H, m), 7.70-7.99(2H, m), 8.05-8.70(1H,
(75.39 6.98 3.03)
I-67 1.30-1.60(2H, m), 2.05-2.32(2H, m), 2.40(2H, t),
C.sub.28 H.sub.33 NO.sub.4. 1/2H.sub.2 O
(2H, t), 3.23(2H, q), 3.79(3H, s), 3.80(6H, s), 3.88
68.35 7.40 2.76
(2H, s), 4.86(2H, s), 5.33(1H, br t), 6.39(2H, s),
(68.21 7.16 2.84)
6.88-7.33(9H, m)
__________________________________________________________________________
TABLE 28
__________________________________________________________________________
(%) Melting
Example
R' R.sup.0
Ar m x Yield
Point (.degree.C.)
__________________________________________________________________________
I-68
##STR340## H
##STR341##
3 1 56 Noncrystal- line powder
I-69
##STR342## H
##STR343##
3 --
99 Oil
I-70
##STR344## H
##STR345##
3 2 55 Noncrystal- line
__________________________________________________________________________
powder
Elemental Analysis
[Found/(Calculated)]
Example
NMR (.delta..sub.ppm, CDCl.sub.3)
C N H
__________________________________________________________________________
I-68 1.00-1.40(8H, m), 1.65-2.40(12H, m), 3.65-3.85(8H,
C.sub.33 H.sub.41 NO.sub.3.HCl.
3/2H.sub.2 O
4.79(2H, s), 6.48(1H, s), 6.80-7.29(10H, m)
70.31 7.78 2.38
(70.38 8.05 2.49)
I-69 1.35-1.75(2H, m), 1.90-2.30(5H, m), 3.15(1H, t),
C.sub.27 H.sub.29 NO.sub.2. 7/10H.sub.2
O
(1H, t), 3.85(1H, d), 3.88(1H, s), 4.40-4.60(2H,
78.78 7.20 3.41
4.84(1H, s), 4.86(1H, s), 6.85-7.38(14H, m)
(79.02 7.47 3.41)
I-70 1.40-1.63(3H, m), 1.90-3.01(11H, m), 3.74(3H, s),
C.sub.31 H.sub.33 NO.sub.2.HCl.
3/2H.sub.2 O
3.91(2H, s), 4.85(2H, s), 6.59(1H, d), 6.66(1H, dd),
72.02 7.10 2.78
6.95-7.30(10H, m) (72.29 7.24 2.72)
__________________________________________________________________________
EXAMPLE II-1
4-{2-[4-(p-Fluorophenyl)piperazin-1-yl]ethyl}-3,4-dihydro-4-phenylisoquinol
ine dihydrochloride
1-[4-(p-Fluorophenyl)piperazin-1-yl]-4-formylamino-3,3-diphenylbutane (7 g)
was heated in polyphosphoric acid (70 g) at 170.degree. C. with stirring
for 2 hours. The reaction mixture was poured in ice-water (500 ml), made
basic with concentrated aqueous ammonia and extracted with ethyl acetate.
The extract was washed with water, dried over anhydrous sodium sulfate and
concentrated to dryness. The residue was purified by silica gel column
chromatography (ethyl acetate) and treated with hydrochloric acid to
provide the title compound (3.5 g) as non-crystalline powder.
Compounds II-2.about.4 and II-6.about.15 were respectively synthesized in
the same manner as Example II-1.
Compound II-2
3,4-Dihydro-4-(3-morpholinopropyl)-4-phenylisoquinoline hydrochloride
Compound II-3
3,4-Dihydro-4-phenyl-4-[3-(phthalimido)propyl]isoquinoline hydrochloride
Compound II-4
3,4-Dihydro-4-[3-(2,3,4,5-tetrahydro-1(H)-3-benzazepin-3-yl]propylisoquinol
ine dihydrochloride
Compound II-6
3,4-Dihydro-4-(3-dimethylaminopropyl)-4-phenylisoquinolin dihydrochloride
Compound II-7
4-[3-(N-Benzyl-N-methyl)aminopropyl]-3,4-dihydro-4-phenylisoquinoline
dihydrochloride
Compound II-8
4-Phenyl-4-[3-(4-phenylpiperazin-1-yl)propyl]isoquinoline
Compound II-9
4-{3-[4-(p-Fluorophenyl)piperazin-1-yl]propyl}-3,4-dihydro-4-phenylisoquino
line dihydrochloride
Compound II-10
4-[3-(4-Benzylpiperazin-1-yl]propyl]-3,4-dihydro-4-phenylisoquinoline
trihydrochloride
Compound II-11
3,4-Dihydro-4-phenyl-4-[3-(4-phenylpiperidin-1-yl]propyl]isoquinoline
dihydrochloride
Compound II-12
4-(p-Chlorophenyl)-3,4-dihydro-4-(3-phthalimidopropyl)isoquinoline
hydrochloride
Compound II-13
4-(p-Chlorophenyl)-3,4-dihydro-4-[3-(4-phenylpiperazino)propyl]isoquinoline
trihydrochloride
Compound II-14
3-(p-Chlorphenyl)-3,4-dihydro-4-[3-(4-phenylpiperidino)propyl]isoquinoline
dihydrochloride
Compound II-15
4-(p-Chlorophenyl)-4-{3-[4-(p-fluorophenyl)-piperazin-1-yl]propyl}-3,4-dihy
droisoquinoline dihydrochloride
EXAMPLE II-5
4-(3-Aminopropyl)-3,4-dihydro-4-phenylisoquinoline dihydrochloride
To a solution of 3,4-dihydro-4-phenyl-4-[3-(phthalimidopropyl)]isoquinoline
(4.1 g) in methanol (100 ml) was added hydrazine hydrate (1.04 g) and the
mixture was refluxed for 22 hours. The reaction mixture was concentrated
to dryness and the residue was dissolved in ethyl acetate--1N aqueous
sodium hydroxide solution. The organic layer was washed with water, dried
over anhydrous sodium sulfate and concentrated to dryness. The residue was
treated with hydrochloric acid to provide the title compound (2 g) as
light-tan non-crystalline powder.
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Tables 29, 30 and 31.
TABLE 29
__________________________________________________________________________
##STR346##
Melting
Example
R' R.sup.0
Ar m x Point (.degree.C.)
__________________________________________________________________________
II-1
##STR347## H
##STR348##
2 2 Noncrystal- line powder
II-2
##STR349## H
##STR350##
3 1 Noncrystal- line powder
II-3
##STR351## H
##STR352##
3 1 140-143
II-4
##STR353## H
##STR354##
4 2 Noncrystal- line powder
II-5 NH.sub.2 H
##STR355##
3 2 Noncrystal- line powder
__________________________________________________________________________
Elemental Analysis
[Found/(Calculated)]
Example NMR (.delta..sub.ppm, CDCl.sub.3)
C N H
__________________________________________________________________________
II-1 2.10-2.50(4H, m), 2.54(4H, t), 3.09
C.sub.27 H.sub.28 FN.sub.3.2HCl. 5/2H.sub.2 O
(4H, t), 3.83(1H, dd), 4.31(1H, dd),
61.35 6.55 7.49
6.80-7.00(4H, m), 7.20-7.50(9H, m),
(61.02 6.64 7.91)
8.31(1H, s).
II-2 1.40-1.70(2H, m), 2.00-2.40(8H, m),
C.sub.22 H.sub.26 N.sub.2 O.HCl.2H.sub.2 O
3.67(2H, t), 3.80(1H, dd), 4.25
62.38 7.62 6.55
(1H, dd), 7.20-7.50(9H, m), 8.30
(62.47 7.39 6.62)
(1H, s).
II-3 1.38-1.58(1H, m), 1.67-1.89(1H, m),
C.sub.26 H.sub.22 N.sub.2 O.sub.2.HCl.
1/2H.sub.2 O
1.94-2.25(2H, m), 3.64(2H, t), 3.77
71.01 5.49 6.16
(1H, dd), 4.25(1H, dd), 7.11-7.45
(70.98 5.50 6.37)
(9H, m), 7.66-7.76(2H, m), 7.77-7.87
(2H, m), 8.28(1H, t)
II-4 1.26(1H, m), 1.58(1H, m), 2.07(2H,
C.sub.28 H.sub.30 N.sub.2.2HCl. 4/5H.sub.2 O
m), 2.41(2H, m), 2.54(4H, m), 2.88
69.93 7.21 5.78
(4H, m), 3.82(1H, dd), 4.27(1h, dd),
(69.78 7.03 5.80)
7.00-7.50(13H, m), 8.30(1H, s).
II-5 1.11-1.38(1H, m), 1.25(2H, br s),
C.sub.18 H.sub.20 N.sub.2.2HCl. 1/2H.sub.2 O
1.40-1.63(1H, m), 2.01-2.12(2H, m),
62.82 7.03 7.51
2.66(2H, t), 3.81(1H, dd), 4.28
(62.43 6.69 8.09)
(1H, dd), 7.14-7.48(9H, m), 8.30
(1H, t)
__________________________________________________________________________
TABLE 30
__________________________________________________________________________
Melting
Example
R' R.sup.0
Ar m x Point (.degree.C.)
__________________________________________________________________________
II-6 N(CH.sub.3).sub.2
H
##STR356##
3 2 155-160
II-7
##STR357## H
##STR358##
3 2 159-164
II-8
##STR359## H
##STR360##
3 --
Syrup
II-9
##STR361## H
##STR362##
3 2 Noncrystal- line powder
II-10
##STR363## H
##STR364##
3 3 150-154
II-11
##STR365## H
##STR366##
3 2 Noncrystal- line powder
__________________________________________________________________________
Elemental Analysis
[Found/(Calculated)]
Example NMR (.delta..sub.ppm, CDCl.sub.3)
C N H
__________________________________________________________________________
II-6 1.12-1.36(1H, m), 1.41-1.63(1H, m),
C.sub.20 H.sub.24 N.sub.2.2HCl. 4/5H.sub.2 O
2.00-2.11(2H, m), 2.14(6H, s),
63.62 7.83 6.89
2.13-2.25(2H, m), 3.81(1H, dd),
(63.26 7.33 7.38)
4.28(1H, dd), 7.15-7.46(9H, m),
8.29(1H, t)
II-7 1.20-1.40(1H, m), 1.46-1.69(1H, m),
C.sub.26 H.sub.28 N.sub.2.2HCl. 1/2H.sub.2 O
2.01-2.12(2H, m), 2.28-2.38(2H, m),
69.60 7.53 5.99
2.10(3H, s), 3.40(2H, s), 3.81
(69.33 6.94 6.22)
(1H, dd), 4.26(1H, dd), 7.13-7.45
(14H, m), 8.30(1H, t)
II-8 1.16-1.41(1H, m), 1.40-1.70(1H, m),
2.00-2.15(2H, m), 2.26-2.41(2H, m),
2.50(4H, t), 3.16(4H, t), 3.82
(1H, dd), 4.27(1H, dd), 6.80-6.95
(3H, m), 7.14-7.46(11H, m), 8.30
(1H, dd)
II-9 1.20-1.70(2H, m), 2.09(2H, m), 2.51
C.sub.28 H.sub.30 FN.sub.5.2HCl.2H.sub.2 O
(4H, m), 3.09(4H, t), 3.83(1H, dd),
63.07 6.90 8.00
4.27(1h, dd), 6.80-7.00(4h, m),
(62.68 6.95 7.83)
7.10-7.50(9H, m), 8.31(1H, s).
II-10 1.20-2.50(14H, m), 3.49(2H, s),
C.sub.29 H.sub.33 N.sub.2.3HCl. 3/2H.sub.2 O
3.80(1H, dd), 4.25(1H, dd), 7.10-
62.53 7.24 7.42
7.40(14H, m), 8.29(1H, s).
(62.20 7.02 7.50)
II-11 1.20(2.60 (13H, m), 2.95(2H, br d),
C.sub.29 H.sub.32 N.sub.2.2HCl.2H.sub.2 O
3.83(1H, dd), 4.27(1H, dd), 7.10-
67.46 7.25 5.47
7.50(14H, m), 8.31(1H, br s).
(67.30 7.40 5.41)
__________________________________________________________________________
TABLE 31
- Elemental Analysis
Melting [Found/(Calculated)]
Example R' R.sup.2 Ar m x point (.degree.C.) NMR (.delta..sub.ppm,
CDCl.sub.3) C H
N
II-12
##STR367##
H
##STR368##
3 1 136-141
##STR369##
##STR370##
II-13
##STR371##
H
##STR372##
3 3 164-169
##STR373##
##STR374##
II-14
##STR375##
H
##STR376##
3 2 165-170
##STR377##
##STR378##
II-15
##STR379##
7-Cl
##STR380##
3 2
##STR381##
##STR382##
##STR383##
EXAMPLE III-1
1,2,3,4-Tetrahydro-4-{2-[4-(p-fluorophenyl)-piperazin-1-yl]ethyl}-4-phenyli
soquinoline dihydrochloride
To a solution of
4-{2-[4-(p-fluorophenyl)piperazin-1-yl]ethyl}-3,4-dihydro-4-phenylisoquino
line (3.1 g) in ethanol (50 ml) was added sodium borohydride (0.774 g) and
the mixture was stirred at room temperature for 1 hour. The reaction
mixture was dissolved in iced water (50 ml) and extracted with ethyl
acetate. The extract was washed with water, dried over anhydrous sodium
sulfate and concentrated to dryness. The residue was purified by silica
gel column chromatography (ethyl acetate) and treated with hydrochloric
acid to provide the title compound (3.0 g) as non-crystalline powder.
Compounds III-2, III-4, III-7 and III-9.about.15 were respectively
synthesized in the same manner as Example III-1.
Compound III-2
1,2,3,4-Tetrahydro-4-(3-morpholinopropyl)-4-phenylisoquinoline
dihydrochloride
Compound III-4
1,2,3,4-Tetrahydro-4-[3-(2,3,4,5-tetrahydro-1(H)-3-benzazepin-3-yl)]propyl-
4-phenylisoquinoline dihydrochloride
Compound III-7
4-[3-(N-Benzyl-N-methyl)aminopropyl]-1,2,3,4-tetrahydro-4-phenylisoquinolin
e dihydrochloride
Compound III-9
4-{3-[4-(p-fluorophenyl)piperazin-1-yl]propyl}-1,2,3,4-tetrahydro-4-phenyli
soquinoline dihydrochloride
Compound III-10
4-[3-(4-Benzylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydro-4-phenylisoquinolin
e trihydrochloride
Compound III-11
1,2,3,4-Tetrahydro-4-phenyl-4-[3-(4-phenylpiperidino)propyl]isoquinoline
dihydrochloride
Compound III-13
4-(p-Chlorophenyl)-1,2,3,4-tetrahydro-4-[3-(4-phenylpiperazin-1-yl)propyl]i
soquinoline dihydrochloride
Compound III-14
4-(p-Chlorophenyl)-1,2,3,4-tetrahydro-4-[3-(4-phenylpiperidino)propyl]isoqu
inoline dihydrochloride
Compound III-15
4-(p-Chlorophenyl)-4-{3-[4-(p-fluorophenyl)piperazin-1-yl]propyl}-1,2,3,4-t
etrahydroisoquinoline dihydrochloride
EXAMPLE III-3
1,2,3,4-Tetrahydro-4-phenyl-4-[3-(phthalimido)propyl]isoquinoline
hydrochloride
To a solution of 3,4-dihydro-4-phenyl-4-[3(phthalimido)propyl]isoquinoline
(1 g) in ethanol (30 ml) was added 10% palladium-on-carbon (0.3 g) and
hydrogenation was carried out at atmospheric pressure and temperature for
5 hours. The catalyst was then filtered off and the filtrate was
concentrated to dryness. The residue was treated with hydrochloric acid to
provide the title compound (0.77 g) as light-yellow powder.
Compounds III-5, 6, 8 and 12 were respectively synthesized in the same
manner as Example III-3.
Compound III-5
4-(3-Aminopropyl)-1,2,3,4-tetrahydro-4-phenylisoquinoline dihydrochloride
Compound III-6
4-[3-(Dimethylamino)propyl]-1,2,3,4-tetrahydro-4'-phenylisoquinoline
dihydrochloride
Compound III-8
1,2,3,4-Tetrahydro-4-phenyl-4-[3-(4-phenylpiperazin-1-yl)propyl]isoquinolin
e trihydrochloride
Compound III-12
4-(p-Chlorophenyl)-1,2,3,4-tetrahydro-4-[3(phthalimido)propyl]isoquinoline
The structural formulas, physical properties and NMR spectra of the above
compounds are shown in Tables 32, 33 and 34.
TABLE 32
-
##STR384##
Elemental Analysis
Melting [Found/(Calculated)]
Example R' R.sup.0 Ar m x Point (.degree.C.) NMR (.delta..sub.ppm,
CDCl.sub.3) C H
N
III-1
##STR385##
H
##STR386##
2 2
##STR387##
##STR388##
##STR389##
III-2
##STR390##
H
##STR391##
3 2
##STR392##
##STR393##
##STR394##
III-3
##STR395##
H
##STR396##
3 1 146-150
##STR397##
##STR398##
III-4
##STR399##
H
##STR400##
3 2
##STR401##
##STR402##
##STR403##
III-5 NH.sub.2 H
##STR404##
3 2 169-173
##STR405##
##STR406##
III-6 N(CH.sub.3).sub.2 H
##STR407##
3 2 148-153
##STR408##
##STR409##
TABLE 33
- Elemental Analysis
Melting [Found/(Calculated)]
Example R' R.sup.0 Ar m x Point (.degree.C.) NMR (.delta..sub.ppm,
CDCl.sub.3) C H
N
III-7
##STR410##
H
##STR411##
3 2 150-155
##STR412##
##STR413##
III-8
##STR414##
H
##STR415##
3 3 175-179
##STR416##
##STR417##
III-9
##STR418##
H
##STR419##
3 2 139-140
##STR420##
##STR421##
III-10
##STR422##
H
##STR423##
3 3 160-165
##STR424##
##STR425##
III-11
##STR426##
H
##STR427##
3 2 164-169
##STR428##
##STR429##
III-12
##STR430##
H
##STR431##
3 -- 139-143
##STR432##
##STR433##
III-13
##STR434##
H
##STR435##
3 2 165-170
##STR436##
##STR437##
TABLE 34
- Elemental Analysis
Melting [Found/(Calculated)]
Example R' R.sup.0 Ar m x Point (.degree.C.) NMR (.delta..sub.ppm,
CDCl.sub.3) C H
N
III-14
##STR438##
H
##STR439##
3 2 182-187
##STR440##
##STR441##
III-15
##STR442##
7-Cl
##STR443##
3 2
##STR444##
##STR445##
##STR446##
EXAMPLE IV-1
4-{2-[4-(p-Fluorophenyl)piperazin-1-yl]ethyl}-1,2,3,4-tetrahydro-2-methyl-4
-phenylisoquinoline hydrochloride
To a solution of
4-{2-[4-(p-fluorophenyl)piperazin-1-yl]ethyl}-1,2,3,4-tetrahydro-4-phenyli
soquinoline (0.6 g) in ethanol (15 ml) was added 37% formalin (1 ml) as
well as 10% palladium-on-carbon (0.25 g) and the mixture was stirred in
hydrogen streams at atmospheric pressure and room temperature for 3 hours.
The catalyst was then filtered off and the filtrate was concentrated to
dryness. The residue was purified by silica gel column chromatography
(ethyl acetate) and treated with hydrochloric acid to provide the title
compound (0.43 g) as non-crystakkube powder.
Compounds IV-2, 7, 8 and 9 were respectively synthesized in the same manner
as Example IV-1.
Compound IV-2
1,2,3,4-Tetrahydro-2-methyl-4-phenyl-4-[3-(phthalimido)propyl]isoquinoline
hydrochloride
Compound IV-7
1,2,3,4-Tetrahydro-2-methyl-4-phenyl-4-[3-(4-phenylpiperazin-1-yl)propyl]is
oquinoline trihydrochloride
Compound IV-8
4-{3-[4-(p-Fluorophenyl)piperazin-1-yl]propyl}-1,2,3,4-tetrahydro-2-methyl-
4-phenylisoquinoline trihydrochloride
Compound IV-9
4-(p-Chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-4-[(3-phthalimido)propyl]iso
quinoline hydrochloride
EXAMPLE IV-3
4-(3-Aminopropyl)-1,2,3,4-tetrahydro-2-methyl-4-phenylisoquinoline
hydrochloride
2-Methyl-4-phenyl-4-[3-(phthalimido)propyl]-1,2,3,4-tetrahydroisoquinoline
(2 g) was heated in methanol (50 ml) under reflux in the presence of
hydrazine hydrate (0.5 g) for 17 hours. The reaction mixture was
concentrated to dryness and the residue was dissolved in ethyl acetate -
1N sodium hydroxide solution. The organic layer was washed with water,
dried over anhydrous sodium sulfate and concentrated to dryness. The
residue was treated with hydrochloric acid to provide the title compound
(1.5 g) as white powder.
Compound IV-10 was synthesized in the same manner as Example IV-3.
Compound IV-10
4-(3-Aminopropyl)-4-(chlorophenyl)-1,2,3,4-tetrahydro-2-methylisoquinoline
hydrochloride
EXAMPLE IV-4
4-[3-Benzylamino)propyl]-1,3,3,4-tetrahydro-2-methyl-4-phenylisoquinoline
hydrochloride
To a solution of
4-(3-aminopropyl)-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (0.4 g)
and benzaldehyde (0.76 g) in ethanol (15 ml) was added 10%
palladium-on-carbon (0.15 g) and hydrogenation was carried out at
atmospheric temperature and room temperature overnight. From this reaction
mixture the catalyst was filtered off and the filtrate was concentrated to
dryness. The residue was purified by silica gel column chromatography and
treated with hydrochloric acid to provide the title compound (0.38 g) as
light-yellow powder.
EXAMPLE IV-5
1,2,3,4-Tetrahydro-2-methyl-4-phenyl-4-[3-(phenylureido]propyl]isoquinoline
To a solution of
4-(3-aminopropyl)-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (0.4 g)
in chloroform (10 ml) was added phenyl isocyanate (0.25 g) and the mixture
was stirred at room temperature for 1.5 hours. The reaction mixture was
concentrated to dryness and the residue was crystallized from
methanolisopropyl ether to provide the title compound (0.39 g) as
colorless powder.
Compound IV-6 and IV-24 was synthesized in the same manner as Example IV-5.
Compound IV-6
1,2,3,4-Tetrahydro-2-methyl-4-[3-(3-methoxyphenylureido)propyl]-4-phenyliso
quinoline
Compound IV-24
1,2,3,4-Tetrahydro-2-methyl-4-[3-phenylthioureido)propyl]-4-phenylisoquinol
ine
EXAMPLE IV-12
4-(p-Chlorophenyl)-2-methyl-4-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,3,4-te
trahydroisoquinoline hydrochloride
To a solution of
4-(p-chlorophenyl)-4-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydro
isoquinoline (0.7 g) in acetonitrile (15 ml) was added formalin (0.64 ml).
Then, sodium cyanoborohydride (0.16 g) was added portionwise with
stirring. The mixture was stirred for 15 minutes, at the end of which time
acetic acid was added dropwise until the solution became neutral. The
mixture was further stirred for 2 hours and the reaction mixture was
extracted with ethyl acetate-1N aqueous sodium hydroxide solution. The
organic layer was washed with water, dried over anhydrous sodium sulfate
and concentrated to dryness. The residue was purified by silica gel column
chromatography and treated with hydrochloric acid to provide the title
compound (0.6 g) as colorless powder.
Compounds IV-11, 13 and 14 were respectively synthesized in the same manner
as Example IV-12.
Compound IV-11
4-(p-Chlorophenyl)-4-[3-(2-hydroxymethylbenzoylamino)propyl]-2-methyl-1,2,3
,4-tetrahydroisoquinoline hydrochloride
Compound IV-13
4-(p-Chlorophenyl)-2-methyl-4-[3-(4-phenylpiperidino)propyl]-1,2,3,4-tetrah
ydroisoquinoline trihydrochloride
Compound IV-14
4-(p-Chlorophenyl)-4-{3-[4-(p-fluorophenyl)piperidino]propyl}-2-methyl-1,2,
3,4-tetrahydroisoquinoline trihydrochloride
EXAMPLE IV-15
4-[3-(4-Benzylpiperazin-1-yl)propyl]-4-phenyl-2-propyl-1,2,3,4,-tetrahydroi
soquinoline hydrochloride
To a solution of
4-[3-(4-benzylpiperazin-1-yl)propyl]-4-phenyl-1,2,3,4-tetrahydroisoquinoli
ne (0.62 g) in a mixture of acetonitrile (20 ml) and DMF (10 ml) were added
3-iodopropane (0.26 g) and potassium carbonate (0.38 g) and the mixture
was stirred at room temperature for 2 days. The reaction mixture was
concentrated to dryness and dissolved in water-ethyl acetate. The ethyl
acetate layer was washed with water, dried over anhydrous sodium sulfate
and concentrated to dryness. The residue was purified by silica gel column
chromatography (chloroform-methanol=15:1) and treated with hydrochloric
acid to provide the title compound (0.6 g) as non-crystalline powder.
Compound IV-16 was synthesized in the same manner as Example IV-15.
Compound IV-16
2-Benzyl-1,2,3,4-tetrahydro-4-[3-(morpholino)propyl]-4-phenylisoquinoline
dihydrochloride
EXAMPLE IV-17
2-Acetyl-4-phenyl-4-{2-[4-(p-fluorophenyl)-piperazin-1-yl]propyl}-1,2,3,4-t
etrahydroisoquinoline hydrochloride
To a solution of
4-phenyl-4-{2-[4-(p-fluorophenyl)piperazin-1-yl]propyl}-1,2,3,4-tetrahydro
isoquinoline (1.2 g) in methylene chloride (30 ml) was added acetic
anhydride (0.33 ml) with ice-cooling and stirring and the mixture was
further stirred at room temperature for 1 hour. The reaction mixture was
then concentrated to dryness and the residue was purified by silica gel
column chromatography (ethyl acetate-methanol=10:1) and treated with
hydrochloric acid to provide the title compound (1.2 g) as white crystals.
Compounds IV-18, 21, 22 and 23 were synthesized in the same manner as
Example IV-17.
Compound IV-18
2-(p-Bromobenzoyl)-4-(p-chlorophenyl)-1,2,3,4-tetrahydro-4-[2-(4-phenylpipe
razin-1-yl)propyl]isoquinoline dihydrochloride
Compound IV-21
2-Methanesulfonyl-4-phenyl-1,2,3,4-tetrahydro-4-{3-[2,3,4,5-tetrahydro-1-(H
)-3-benzazepin-3-yl]propyl}isoquinoline dihydrochloride
Compound 22
2-(2-Methylenesulfonyl)-4-phenyl-1,2,3,4-tetrahydro-4-{3-[4-(p-fluorophenyl
)piperazin-1-yl]propyl}isoquinoline hydrochloride
Compound 23
2-Methoxycarbonyl-4-(p-chlorophenyl)-1,2,3,4-tetrahydro-4-{3-[4-(p-fluoroph
enyl)piperazin-1-yl]propyl}isoquinoline hydrochloride
EXAMPLE IV-19
4-[3-(N-Benzyl-N-methylamino)propyl]-4-phenyl-2-phenylcarbamoyl-1,2,3,4-tet
rahydroisoquinoline hydrochloride
To a solution of
4-[3-(N-benzyl-N-methylamino)propyl]-4-phenyl-1,3,3,4-tetrahydroisoquinoli
ne (0.8 g) in chloroform (20 ml) was added phenyl isocyanate (0.38 g) and
the mixture was stirred at room temperature for 1.5 hours. The reaction
mixture was concentrated to dryness and the residue was purified by silica
gel column chromatography. The resulting syrup was treated with
hydrochloric acid to provide the title compound (0.8 g) as colorless
powder.
Compound IV-20 was synthesized in the same manner as Example IV-19.
Compound IV-20
1,2,3,4-Tetrahydro-4-{2-[4-(p-fluorophenyl)-piperazin-1-yl]ethyl}-2-(3-meth
oxyphenyl)carbamoyl-4-phenylisoquinoline hydrochloride
The structural formulas, physical properties and NMR spectra of the
respective compounds are shown in Tables 35, 36, 37, 38, 39 and 40.
TABLE 35
-
##STR447##
Elemental Analysis
Melting [Found/(Calculated)]
Example R' R.sup.0 R" Ar m x Point (.degree.C.) NMR (.delta..sub.ppm,
CDCl.sub.3) C H
N
IV-1
##STR448##
H CH.sub.3
##STR449##
2 2
##STR450##
##STR451##
##STR452##
IV-2
##STR453##
H CH.sub.3
##STR454##
3 1 191-194
##STR455##
##STR456##
IV-3 NH.sub.2 H CH.sub.3
##STR457##
3 2 183-189
##STR458##
##STR459##
IV-4
##STR460##
H CH.sub.3
##STR461##
3 2 157-162
##STR462##
##STR463##
TABLE 36
- Elemental Analysis
Melting [Found/(Calculated)]
Example R' R.sup.0 R" Ar m x Point (.degree.C.) NMR (.delta..sub.ppm,
CDCl.sub.3) C H
N
IV-5
##STR464##
H CH.sub.3
##STR465##
3 -- 143-146
##STR466##
##STR467##
IV-6
##STR468##
H CH.sub.3
##STR469##
3 -- 153-155
##STR470##
##STR471##
IV-7
##STR472##
H CH.sub.3
##STR473##
3 3 168-172
##STR474##
##STR475##
IV-8
##STR476##
H CH.sub.3
##STR477##
3 3 139-140
##STR478##
##STR479##
TABLE 37
- Elemental Analysis
Melting [Found/(Calculated)]
Example R' R.sup.0 R" Ar m x Point (.degree.C.) NMR (.delta..sub.ppm,
CDCl.sub.3) C H
N
IV-9
##STR480##
H CH.sub.3
##STR481##
3 1 176-181
##STR482##
##STR483##
IV-10 NH.sub.2 H CH.sub.3
##STR484##
3 2 184-190
##STR485##
##STR486##
IV-11
##STR487##
H CH.sub.3
##STR488##
3 1 147-152
##STR489##
##STR490##
IV-12
##STR491##
H CH.sub.3
##STR492##
3 3 176-182
##STR493##
##STR494##
IV-13
##STR495##
H CH.sub.3
##STR496##
3 2 172-177
##STR497##
##STR498##
TABLE 38
- Elemental Analysis
Melting [Found/(Calculated)]
Example R' R.sup.0 R" Ar m x Point (.degree.C.) NMR (.delta..sub.ppm,
CDCl.sub.3) C H
N
IV-14
##STR499##
7-Cl CH.sub.3
##STR500##
3 3 163-168
##STR501##
##STR502##
IV-15
##STR503##
H .sup.n
Pr
##STR504##
3 3
##STR505##
##STR506##
##STR507##
IV-16
##STR508##
H Bn
##STR509##
3 2
##STR510##
##STR511##
##STR512##
IV-17
##STR513##
H Ac
##STR514##
3 2 118-120
##STR515##
##STR516##
IV-18
##STR517##
H
##STR518##
##STR519##
3 2 142-146
##STR520##
##STR521##
TABLE 39
- Elemental Analysis
Melting [Found/(Calculated)]
Example R' R.sup.0 R" Ar m x Point (.degree.C.) NMR (.delta..sub.ppm,
CDCl.sub.3) C H
N
IV-19
##STR522##
H
##STR523##
##STR524##
3 1 189-192
##STR525##
##STR526##
IV-20
##STR527##
H
##STR528##
##STR529##
3 1 144-147
##STR530##
##STR531##
IV-21
##STR532##
H SO.sub.2
Me
##STR533##
3 1
##STR534##
##STR535##
##STR536##
TABLE 40
- Elemental Analysis
(%) Melting [Found/(Calculated)]
Example R' R.sup.0 R" Ar m x Yield Point (.degree.C.) NMR (.delta..sub.p
pm, in CDCl.sub.3) C H
N
IV-22
##STR537##
H
##STR538##
##STR539##
4 -- 55
##STR540##
##STR541##
##STR542##
IV-23
##STR543##
H CO.sub.2
Me
##STR544##
3 1 63 123-128
##STR545##
##STR546##
IV-24
##STR547##
H CH.sub.3
##STR548##
3 -- 65
##STR549##
##STR550##
##STR551##
FORMULATION EXAMPLE 1
______________________________________
(1) Compound of Example I-45
10.0 g
(2) Lactose 60.0 g
(3) Corn starch 35.0 g
(4) Gelatin 3.0 g
(5) Magnesium stearate 2.0 g
______________________________________
Using 30 ml of an aqueous solution of gelatin (10% by weight, 3.0 g as
gelatin), a mixture of 10.0 g of the compound obtained in Example 1-45,
60.0 g of lactose and 35.0 g of corn starch was granulated through a 1
mm-mesh sieve, dried at 40.degree. C., and resieved. To the granulation
thus obtained was added 2.0 g of magnesium stearate and the mixture was
compressed. The core tablets thus prepared were coated with a coating
composition comprising an aqueous suspension of sucrose, titanium dioxide,
talc and gum arabic and, then, grazed with beeswax to provide 1000 coated
tablets.
FORMULATION EXAMPLE 2
______________________________________
(1) Compound of Example I-45
10.0 g
(2) Lactose 70.0 g
(3) Corn starch 50.0 g
(4) Soluble starch 7.0 g
(5) Magnesium stearate 3.0 g
______________________________________
Using 70 ml of an aqueous solution of soluble starch (7.0 g as soluble
starch), a mixture of 10.0 g of the compound obtained in Example 1-45 and
3.0 g of magnesium stearate was granulated. The granulation was dried and
mixed with 70.0 g of lactose and 50.0 g of corn starch. The resulting
composition was compressed to provide 1000 tablets.
FORMULATION EXAMPLE 3
______________________________________
(1) Compound of Example I-36
10.0 g
(2) Lactose 60.0 g
(3) Corn starch 35.0 g
(4) Gelatin 3.0 g
(5) Magnesium stearate 2.0 g
______________________________________
A mixture of 10.0 g of the compound obtained in Example 1-36, 60.0 g of
lactose and 35.0 g of corn starch was passed through a 1 mm mesh sieve and
granulated with 30 ml of 10 wt. % aqueous gelatin solution (3.0 g as
gelatin) and the granulation was dried at 40.degree. C. and re-sieved. The
granules thus prepared were mixed with 2.0 g of magnesium stearate and the
mixture was compressed. The resulting core tablets were coated with an
aqueous suspension containing sucrose, titanium dioxide, talc and gum
arabic. The coated tablets were then grazed with beeswax to provide 1000
tablets.
FORMULATION EXAMPLE 4
______________________________________
(1) Compound of Example I-36
10.0 g
(2) Lactose 70.0 g
(3) Corn starch 50.0 g
(4) Soluble starch 7.0 g
(5) Magnesium stearate 3.0 g
______________________________________
A mixture of 10.0 g of the compound obtained in Example 1-36 and 3.0 g of
magnesium stearate was granulated with 70 ml of an aqueous solution of
soluble starch (7.0 g as soluble starch) and the granulation was dried and
mixed with 70.0 g of lactose and 50.0 g of corn starch. This mixture was
compressed to provide 1000 tablets.
EXPERIMENTAL EXAMPLE 1
(A) Preparation of .sup.125 I-leuprolerin
Ten (10) .mu.l of 3.times.10.sup.4 M aqueous leuprolerin solution and 10
.mu.l of 0.01 mg/ml lactoperoxidase were taken in a tube and 10 .mu.l of
Na.sup.125 I solution (37 MBq) was added. After stirring, 10 .mu.l of
0.001% H.sub.2 O.sub.2 was added and the reaction was conducted at room
temperature for 20 minutes. Then, 700 .mu.l of 0.05% TFA solution was
added to the tube to terminate the reaction and the reaction mixture was
purified by reverse-phase HPLC. The HPLC conditions are shown below.
.sup.125 I-leuprolerin was eluted after a retention time of 26-27 minutes.
Column: TSKgel ODS-80T.sub.M CTR (4.6 mm.times.10 cm)
Eluent: Solvent A (0.05% TFA); Solvent B (40% CH.sub.3 CN-0.05% TFA)
Min. 0 (100% Solvent A)-Min. 3 (100% Solvent
A)-Min. 7 (50% Solvent A+50% Solvent B)-Min. 40 (100% Solvent B)
Elution temperature: room temperature
Elution speed: 1 ml/min.
(B) Preparation of a rat pituitary anterior lobe membrane
fraction containing GnRH receptors
Forty Wistar rats (8 weeks old, male) were sacrificed by decapitation under
no anesthesia and the anterior lobe of the pituitary gland was isolated
and washed with ice-cooled homogenate buffer [25 mM Tris
(tris(hydroxymethyl)aminomethane)-HCl, 0.3M sucrose, 1 mM EGTA
(glycoletherdiamine-N,N,N',N'-tetraacetic acid), 0.25 mM PMSF
(phenylmethylsulfonyl fluoride), 10 U/ml aprotinin, 1 .mu.g/ml pepstatin,
20 .mu.g/ml leupeptin, 100 .mu.g/ml phosphoramidon, 0.03% sodium azide, pH
7.5]. The pituitary tissue was floated in 2 ml of the homogenate buffer
and homogenized using a Polytron homogenizer. The homogenate was
centrifuged at 700.times.G for 15 minutes. The supernatant was taken in an
ultracentrifuge tube and centrifuged at 100,000.times.G for 1 hour to
provide a membrane fraction pellet. This pellet was suspended in 2 ml of
assay buffer [25 mM Tris-HCl, 1 mM EDTA (ethylenediaminetetraacetic acid),
0.1% BSA (bovine serum albumin), 0.25 mM PMSP, 1 .mu.g/ml pepstatin, 20
.mu.g/ml leupeptin, 100 .mu.g/ml phosphoramidon, 0.03% sodium azide, pH
7.5) and the suspension was centrifuged at 100,000.times.G for 1 hour. The
membrane fraction recovered as a pellet was resuspended in 10 ml of assay
buffer, divided into portions, preserved at -80.degree. C. and thawed when
needed.
(C) Preparation of a bovine pituitary anterior lobe membrane fraction
containing GnRH receptors
A bovine pituitary anterior lobe membrane fraction containing GnRH
receptors was prepared by the same procedure as described under (B).
However, a 10,000.times.G centrifugation supernatant was recentrifuged at
100,000.times.G for 1 hour to provide the membrane fraction pellet.
(D) Preparation of a CHO (Chinese hamster ovarian) cell
membrane fraction containing human GnRH receptors
A CHO cell line (109 cells) with human GnRH receptors expressed was
suspended in 5 mM EDTA-supplemented phosphate-buffered physiological
saline (PBS-EDTA) and centrifuged at 100.times.G for 5 minutes. To the
cell pellet was added 10 ml of cell homogenate buffer (10 mM NaHCO.sub.3,
5 mM EDTA, pH 7.5) and the mixture was homogenized using a Polytron
homogenizer. The homogenate was centrifuged at 400.times.G for 15 minutes.
The supernatant was taken in an ultracentrifuge tube and centrifuged at
100,000.times.G for 1 hour to provide a membrane fraction pellet. This
pellet was suspended in 2 ml of assay buffer and centrifuged at
100,000.times.G for 1 hour. The membrane fraction recovered as a pellet
was resuspended in 20 ml of assay buffer, divided into portions, preserved
at -80.degree. C. and thawed when needed.
(E) Determination of the .sup.125 I-leuprolerin binding inhibition rate
For the rat and human membrane fractions prepared in (B) and (D), each
membrane fraction was diluted with assay buffer to a concentration of 200
.mu.g/ml and distributed in 188 .mu.l portions into tubes. As to the
bovine membrane fraction prepared in (C), the membrane fraction was
diluted with assay buffer to 750 .mu.g/ml and distributed in 188 .mu.l
portions into tubes. Where the rat pituitary anterior lobe membrane
fraction was used, 2 .mu.l of a 0.1 mM solution of the compound in 60%
DMSO (dimethyl sulfoxide) and 10 .mu.l of 38 nM .sup.125 -leuprolerin
solution were simultaneously added. Where the bovine pituitary anterior
lobe fraction or the cell membrane fraction of the CHO with human GnRH
receptors expressed, 2 .mu.l of a 2 mM solution of the compound in 60%
DMSO and 10 .mu.l of 38 nM .sup.125 -leuprolerin solution were
simultaneously added. For determining the maximum binding amount, a
reaction system comprising 2 .mu.l of 60% DMSO and 10 .mu.l of 38 nM
.sup.125 I-leuprolerin solution was prepared. On the other hand, for
determining the nonspecific binding amount, a reaction system comprising 2
.mu.l of 100 .mu.M leuprolerin in 60% DMSO and 10 .mu.l of 38 nM .sup.125
I-leuprolerin was also prepared at the same time.
Where the rat or bovine pituitary anterior lobe membrane fraction was used,
the reaction was conducted at 4.degree. C. for 90 minutes. Where the
membrane fraction of the CHO with human GnRH receptors expressed was used,
the reaction was carried out at 25.degree. C. for 60 minutes. After each
reaction, the reaction mixture was filtered under suction through a
polyethyleneimine-treated Whatman glass filter (GF-F). After filtration,
the radioactivity of .sup.125 I-leuprolerin remaining on the filter was
measured with a .gamma.-counter.
The expression (TB-SB)/(TB-NSB).times.100 (where SB=radioactivity with the
compound added, TB=maximum bound radioactivity, NSB=nonspecifically bound
radioactivity) was calculated to find the binding inhibition rate of each
test compound. Furthermore, the inhibition rate was determined by varying
the concentration of the test substance and the 50% inhibitory
concentration (IC.sub.50) of the compound was calculated from Hill plot.
The results are shown in Table 41.
TABLE 41
______________________________________
GnRH receptor binding inhibition test
Example No.
Binding inhibitory activity (IC.sub.50 .mu.M)
of compound
Human Rat Bovine
______________________________________
I-24 -- 0.9 7
I-35 -- 0.7 6
I-36 0 0.6 11
I-37 -- 0.03 6
I-45 6 0.5 5
I-46 -- 0.5 14
I-47 -- 0.3 7
I-48 -- 0.4 10
I-49 -- 0.5 10
I-50 -- 0.08 8
I-51 -- 0.5 10
I-52 6 0.03 5
______________________________________
It is apparent from Table 41 that the compound (I) or salt of this
invention has excellent GnRH receptor binding inhibitory activity.
EXPERIMENTAL EXAMPLE 2
Assay of Monoamine Uptake-antagonizing Activity
(a) Activity to inhibit serotonine (5-HT) uptake
The experiment was performed in accordance with the method of Hyttel et al.
[Psychopharmacology 60, 13, 1978]. The whole brain of a rat was
homogenized in 40 volumes of ice-cooled 0.32M sucrose solution containing
10 .mu.M pargyline and, then, centrifuged (600.times.G) for 10 minutes.
The supernatant was centrifuged (2500.times.G) for 55 minutes to provide a
pellet. This pellet was suspended in Krebs-Ringer-phosphate buffer (pH
7.4; 122 mM NaCl, 4.82 mM KCl, 0.972 mM CaCl.sub.2, 1.21 mM MgSO.sub.4,
12.7 mM Na.sub.2 HPO.sub.4, 2.97 mM NaH.sub.2 PO.sub.4, 0.162 mM EDTA
sodium, 10 mM glucose, 1.14 mM ascorbic acid) saturated with a mixed gas
(95% O and 5% CO.sub.2). To 900 .mu.l of this suspension was added a
solution of the test drug (10 .mu.l ) in DMSO and the mixture was
incubated at 37.degree. C. for 5 minutes. Then, 100 .mu.l of 3H-5-HT
(final concentration 10 nM) was added and the mixture was further
incubated at 37.degree. C. for 5 minutes. This reaction mixture was
filtered under suction using a GF/B filter and the filter was washed with
4 ml of the above-mentioned buffer. The radioactivity on the filter was
measured by the liquid scintillation method.
The amount of the drug which caused a 50% decrease in 5-HT uptake is shown
as 50% inhibitory activity (IC.sub.50) in Table 42.
TABLE 42
______________________________________
Example No. 5-HT uptake inhibitory
of Compound activity (IC.sub.50 .mu.M)
______________________________________
I-6 1.0
I-12 0.022
I-18 0.8
I-24 0.26
I-25 0.14
I-30 0.068
I-33 0.27
I-35 0.13
I-36 0.0051
II-7 0.88
II-8 0.41
II-13 0.14
III-7 0.2
III-8 0.16
III-9 0.17
IV-7 0.18
IV-13 0.13
IV-19 0.23
IV-20 0.03
______________________________________
It is apparent from Table 42 that the compound (I) or salt of this
invention has excellent serotonine uptake antagonizing activity.
(b) Activity to inhibit norepinephrine (NE) uptake
Using the rat cerebral cortex and, as the substrate, .sup.3 H-NE, an
experiment was performed by otherwise the same procedure as described for
5-HT. See Table 43.
TABLE 43
______________________________________
Example No. NE uptake inhibitory
of Compound activity (IC.sub.50 .mu.M)
______________________________________
I-12 0.015
I-24 0.22
I-25 0.39
I-30 0.59
I-33 0.55
I-35 0.30
I-36 0.41
IV-19 0.56
IV-20 0.12
______________________________________
It is apparent from Table 43 that the compound (I) or salt of this
invention has excellent norepinephrine uptake antagonizing activity.
.sup.45 Ca.sup.2+ uptake inhibition experiment
The rat cerebral cortex was homogenized in 10 volumes of ice-cooled 0.32M
sucrose solution to prepare a crude synaptosome fraction (100.times.G, 10
min., 12000.times.G, 20 min.). This fraction was homogenized in Tris
buffer [132 mM sodium chloride, 5 mM potassium chloride, 1.3 mM magnesium
chloride, 1.2 mM sodium dihydrogen phosphate, 1.2 mM calcium chloride, 10
mM glucose; adjusted to pH 7.5 with 20 mM Tris base and saturated with
mixed gas (95% oxygen and 5% carbon dioxide)]. To 900 .mu.l of the
homogenate was added a DMSO solution of the test drug (10 .mu.l ). The
mixture was incubated at 37.degree. C. for 10 minutes, followed by
addition of 100 .mu.l of a veratrine solution (containing 0.18 .mu.ci
.sup.45 Ca.sup.2+) at a final veratrine concentration of M. The mixture
was incubated at 37.degree. C. for 10 minutes, quenched with 4 ml of
ice-cooled EGTA solution (120 mM sodium chloride, 5 mM potassium chloride,
5 mM EGTA, pH=7.5) and suction-filtered using a GF/B filter. The filter
was washed twice with 4 ml each of a washing solution (132 mM sodium
chloride, 5 mM potassium chloride, 1.3 mM magnesium chloride, 1.2 mM
calcium chloride, 20 mM Tris base, pH 7.5) and the radioactivity of the
pooled wash was measured by the liquid scintillation method. The results
are shown in Table 44.
The .sup.45 Ca.sup.2+ uptake inhibition rate was calculated by means of
the following equation.
FORMULA 1
##EQU1##
A: The .sup.45 Ca.sup.2+ uptake after 10 minutes' stimulation with 30
.mu.M veratrine in the presence of the test drug
B: The .sup.45 Ca.sup.2+ uptake in the absence of veratrine and in the
presence of the test drug
C: The .sup.45 Ca.sup.2+ uptake after 10 minutes' stimulation with 30
.mu.M veratrine in the absence of the test drug
D: The .sup.45 Ca.sup.2+ uptake in the absence of the test drug and in the
absence of veratrine
TABLE 44
______________________________________
Example No. .sup.45 Ca.sup.2+ uptake inhibitory
of Compound activity (IC.sub.50 .mu.M)
______________________________________
I-6 0.32
I-12 0.85
I-15 1.25
I-18 1.32
I-19 1.05
I-20 0.94
I-23 0.50
I-24 1.77
I-25 1.19
I-30 1.59
I-33 0.69
I-35 0.14
I-36 0.76
II-7 0.46
II-8 1.84
II-13 1.29
III-7 1.77
III-8 1.63
III-9 1.44
IV-7 1.71
IV-13 0.32
IV-19 0.95
IV-20 0.17
______________________________________
It is apparent from Table 44 that the objective compound (I) or salt of
this invention has excellent calcium ion uptake antagonizing activity.
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